N9 -cyclopentyl-substituted adenine derivatives useful as adenosine receptor agonists

ABSTRACT

The compound of the formula I ##STR1## wherein R, R 3  and R 5  independently represent hydrogen or hydroxy provided that at least one of R, R 3  and R 5  represents hydroxy; R 1  represents hydrogen, lower alkyl, C 3  -C 7  -alkenyl, hydroxy-lower alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkyl-lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, adamantyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl-lower alkyl, tetrahydrothiopyranyl-lower alkyl, adamantyl-lower alkyl, aryl-hydroxy-lower alkyl, aryl, aryl-lower alkyl, aryl-C 3  -C 6  -cycloalkyl, 9-fluorenyl, 9-fluorenyl-lower alkyl or cycloalkenyl-lower alkyl; or R 1  represents a bicyclic benzo-fused 5 or 6-membered saturated carbocyclic radical or a benz-fused 5 or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur directly attached to the fused benzene ring, any said bicyclic radicals being optionally substituted on the benzo portion by lower alkyl, lower alkoxy or halogen, or R 1  represents any said bicyclic radical substituted-lower alkyl; R 2  represents hydrogen, halogen, --S--R 1  &#39;, --NR b  --R 1  &#39;, or --NH--R 1  &#39; in each of which R 1  &#39; has meaning as defined for R 1  provided that R 1  &#39; in --SR 1  &#39; does not represent hydrogen; R b  represents lower alkyl; R 4  represents hydroxymethyl provided that R 2  does not represent either hydrogen or --NHR 1  &#39; in which R 1  &#39; represents either hydrogen or lower alkyl; or R 4  represents lower alkoxymethyl or lower alkylthiomethyl; or R 4  represents --CONHR 6  in which R 6  represents lower alkyl, aryl-lower alkyl, C 3  -C 6  -cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof; methods for their preparation; and their use as adenosine receptor agonists are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 193,969 filed May 13,1988, now U.S. Pat. No. 4,954,504, which is a continuation-in-partapplication of application Ser. No. 137,554 filed Dec. 23, 1987, nowabandoned, which is a continuation-in-part of application Ser. No.931,327 filed Nov. 14, 1986, now abandoned.

SUMMARY OF THE INVENTION

The instant invention is directed to certain functionalized N₉-cyclopentyl-substituted adenine derivatives as adenosine receptorligands, to pharmaceutical compositions thereof, to methods for theirpreparation, and to their use in mammals as therapeutically effectiveadenosine receptor agonists.

The compounds of the invention are effective as adenosine, particularlyadenosine-2 (A-2), receptor ligands which are useful in mammals asadenosine receptor agonists, particularly as adenosine-2 (A-2) receptoragonists.

Said advantageous properties render the compounds of the inventionuseful for the treatment of conditions in mammals responsive toselective adenosine receptor stimulation, particularly to adenosine-2receptor stimulation, e.g. cardiovascular conditions such ashypertension, thrombosis and atherosclerosis, also central nervoussystem conditions comprising psychotic conditions such as schizophrenia,and convulsive disorders such as epilepsy.

The compounds of the invention are structurally related to the naturalproduct aristeromycin which is cited, e.g. in the Journal of OrganicChemistry, Vol. 51, [pp. 1287-1293 (1986) and publications referred totherein, and which is characterized in the literature as a carbocyclicanalog of adenosine.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, the instant invention is directed to the compounds ofthe formula I ##STR2## wherein R, R₃ and R₅ independently representhydrogen or hydroxy provided that at least one of R, R₃ and R₅represents hydroxy; R₁ represents hydrogen, lower alkyl, C₃ -C₇-alkenyl, hydroxy-lower alkyl, optionally substituted cycloalkyl oroptionally substituted cycloalkyl-lower alkyl, bicycloalkyl,bicycloalkyl-lower alkyl, adamantyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydropyranyl-lower alkyl,tetrahydrothiopyranyl-lower alkyl, adamantyl-lower alkyl,aryl-hydroxy-lower alkyl, aryl, aryl-lower alkyl, aryl-C₃ -C₆-cycloalkyl, 9-fluorenyl, 9-fluorenyl-lower alkyl or cycloalkenyl-loweralkyl; or R₁ represents a bicyclic benzo-fused 5 or 6-membered saturatedcarbocyclic radical or a benzo-fused 5 or 6-membered saturatedheterocyclic radical containing a heteroatom selected from oxygen andsulfur directly attached to the fused benzene ring, any said bicyclicradicals being optionally substituted on the benzo portion by loweralkyl, lower alkoxy or halogen, or R₁ represents any said bicyclicradical substituted-lower alkyl; R₂ represents hydrogen, halogen, --S-R₁', --NR_(b) -R₁ ', or --NH-R₁ ' in each of which R₁ ' has meaning asdefined for R₁ provided that R₁ ' in --SR₁ ' does not representhydrogen; R_(b) represents lower alkyl; R₄ represents hydroxymethylprovided that R₂ does not represent either hydrogen or --NHR₁ ' in whichR₁ ' represents either hydrogen or lower alkyl; or R₄ represents loweralkoxymethyl or lower alkylthiomethyl; or R₄ represents --CONHR₆ inwhich R₆ represents lower alkyl, aryl-lower alkyl, C₃ -C₆ -cycloalkyl orhydroxy-lower alkyl; pharmaceutically acceptable ester derivativesthereof in which free hydroxy groups are esterified in form of apharmaceutically acceptable ester; and pharmaceutically acceptable saltsthereof.

Preferred are the compounds of formula I wherein R represents hydrogenor hydroxy; R₁ represents hydrogen, lower alkyl, cycloalkenyl-loweralkyl, C₃ -C₇ -cycloalkyl or C₃ -C₇ -cycloalkyl-lower alkyl whereincycloalkyl is unsubstituted or may be substituted by lower alkyl,hydroxy, lower alkoxy or by a substituent W-Z in which W represents adirect bond or lower alkylene, and Z represents carboxy, carboxyderivatized in the form of a pharmaceutically acceptable ester orcarboxy derivatized in the form of a pharmaceutically acceptable amide;or R₁ represents aryl, aryl-hydroxy-lower alkyl or aryl-lower alkylwherein aryl represents thienyl, pyridyl, naphthyl, phenyl, or phenylsubstituted by one to three of halogen, trifluoromethyl, lower alkoxy,lower alkyl or by a substituent --W--Z in which W represents a directbond, lower alkylene, or oxy-lower alkylene, and Z represents hydroxy,cyano, carboxy, carboxy derivatized in the form of a pharmaceuticallyacceptable ester or carboxy derivatized in the form of apharmaceutically acceptable amide; or R₁ represents a substituent of theformula B ##STR3## in which A represents methylene, oxy or thio, mrepresents zero or one, p represents zero, one or two, and R_(a)represents hydrogen, lower alkyl, lower alkoxy or halogen; R₂ representshydrogen, halogen, --SR₁ ', NR_(b) -R₁ ', or --NHR₁ ' in which R₁ ' hasmeaning as defined for R₁ except that R₁ ' in SR₁ ' does not representhydrogen; R_(b) represents lower alkyl; R₃ represents hydrogen orhydroxy; R₄ represents lower alkoxymethyl or lower alkylthiomethyl; orR₄ represents hydroxymethyl provided that R₂ does not represent eitherhydrogen or --NHR₁ ' in which R₁ ' represents hydrogen or lower alkyl;or R₄ represents --CONHR₆ in which R₆ represents lower alkyl, aryl-loweralkyl, C₃ -C₆ -cycloalkyl or hydroxy-lower alkyl; R₅ represents hydroxy;pharmaceutically acceptable ester derivatives thereof in which one ormore free hydroxy groups are esterified in form of a pharmaceuticallyacceptable ester; and pharmaceutically acceptable salts thereof.

A particular embodiment of the invention relates to the compounds offormula I cited hereinabove wherein R₄ represents --CONHR₆, and R, R₁,R₁ ', R₂, R₃, R₅, R₆, R_(b), m, p and R_(a) have meaning as definedabove; pharmaceutically acceptable ester derivatives thereof as definedabove; and pharmaceutically acceptable salts thereof.

Another particular embodiment relates to the compounds of formula Iwherein R₄ represents hydroxymethyl, and R, R₁, R₁ ', R₂, R₃, R₅, R₆,R_(b), m, p and R_(a) have meaning as defined above, pharmaceuticallyacceptable ester derivatives as defined above; and pharmaceuticallyacceptable salts thereof.

Further embodiments of the invention relate to the compounds citedhereinabove wherein in formula I R, R₂ -R₅ have meaning as defined above(R₁ ' being defined in terms of meaning of R₁ as given above); and NHR₁represents amino (NH₂).

Preferred are the compounds of formula Ia ##STR4## wherein R₂ 'represents NR_(b) '-R₁ ' or NHR₁ '; R₁ ' represents cyclohexenyl-loweralkyl, C₃ -C₆ -cycloalkyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl,4-tetrahydropyranyllower alkyl, 4-tetrahydrothiopyranyl-lower alkyl,adamantyl-lower alkyl, C₃ -C₆ -cycloalkyl-lower alkyl, aryl oraryl-lower alkyl in which aryl represents thienyl, pyridyl, phenyl orphenyl substituted by one to three of halogen, trifluoromethyl, loweralkoxy, lower alkyl or by a substituent --W--Z in which W represents adirect bond, lower alkylene or oxy-lower alkylene, and Z representshydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- orN,N-di-lower alkylcarbamoyl; or R₁ ' represents a substituent of theformula B' ##STR5## in which A' represents a direct bond, methylene, oxyor thio, p represents zero, one or two, and R_(a) ' represents hydrogen,lower alkyl, lower alkoxy or halogen; R₃ ' represents hydrogen orhydroxy; R_(b) ' represents lower alkyl; pharmaceutically acceptableprodrug ester derivatives thereof in which one or more free hydroxygroups are esterified in form of a pharmaceutically acceptable ester;and pharmaceutically acceptable salts thereof.

Preferred are the compounds of formula Ia above wherein R₂ ' representsNR_(b) '-R₁ ' or NHR₁ '; R_(a) ' represents hydrogen; R₃ ' representshydroxy; and R₁ ', R_(b) ', p and A' have meaning as defined above;pharmaceutically acceptable prodrug ester derivatives thereof in whichone or more free hydroxy groups are esterified in form of apharmaceutically acceptable ester; and pharmaceutically acceptable saltsthereof.

Further preferred are the compounds of formula Ib ##STR6## wherein R₂ 'represents NH(CH₂)_(n) --(C₅ or C₆)-cycloalkyl, NR_(b) '-(CH₂)_(n) --(C₅or C₆)-cycloalkyl, NH(CH₂)_(n) --Ar or NR_(b) '-(CH₂)_(n) --Ar in whichn represents zero or the integer 1,2 or 3, R_(b) ' represents C₁ -C₃-alkyl, and Ar represents 2-, 3- or 4-pyridyl, phenyl or phenylsubstituted by one or two of halogen, trifluoromethyl, lower alkoxy,lower alkyl or by a substituent --W--Z in which W represents a directbond, straight chain C₁ -C₄ -alkylene or oxy-C₁ -C₃ -alkylene and Zrepresents hydroxy, cyano, carboxy, lower alkoxycarbonyl, carbamoyl,N-mono- or N,N-di-lower alkylcarbamoyl; R₇, R₇ ' and R₈ independentlyrepresent hydrogen, lower alkanoyl, lower alkoxy-lower alkanoyl, aroyl,carbamoyl, mono- or di-lower alkylcarbamoyl; and pharmaceuticallyacceptable salts thereof.

Particularly preferred are said compounds of formula Ib wherein R₂ 'represents NH(CH₂)_(n) --cyclohexyl or NH(CH₂)_(n) --Ar in which Arpresents phenyl or phenyl monosubstituted by halogen, trifluoromethyl,lower alkoxy, lower alkyl or by a substituent --W--Z in which Wrepresents a direct bond, methylene or ethylene, and Z represents cyano,carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-loweralkylcarbamoyl; n represents zero or the integer 1, 2 or 3.

Particular embodiments thereof relate to the said compounds of formulaIb wherein n represents the integer 2 and wherein n represents zero.

Preferred in turn are the compounds of formula Ib wherein R₂ 'represents NH-Ar in which Ar represents 2-, 3- or 4-pyridyl, phenyl orphenyl substituted by halogen, trifluoromethyl, lower alkoxy, loweralkyl, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- orN,N-di-lower alkylcarbamoyl; R₇, R₇ ' and R₈ independently representhydrogen, lower alkanoyl or lower alkoxy-lower alkanoyl; andpharmaceutically acceptable salts thereof.

Further preferred are said compounds wherein Ar represents phenyl,phenyl monosubstituted by halogen, lower alkyl, lower alkoxy, carboxy orlower alkoxycarbonyl; R₇, R₇ ' and R₈ represent hydrogen; andpharmaceutically acceptable salts thereof

A particular embodiment of the invention relates to the compounds offormula Ic ##STR7## wherein R₇, R₇ ' and R₈ represent hydrogen or loweralkanoyl; R₉ represents hydrogen or methyl; R₁₀ represents hydrogen ormethyl; R₁₁ represents 1-cyclohexenyl, cyclohexyl or cyclohexylsubstituted by lower alkyl, hydroxy, lower alkoxy or by a substituentW--Z in which W represents a direct bond, CH₂ or CH₂ CH₂, and Zrepresents carboxy or lower alkoxycarbonyl; or R₁₁ represents 2-, 3-or4-pyridyl, phenyl or phenyl monosubstituted by halogen, lower alkyl,lower alkoxy or W--Z wherein Z represents carboxy or loweralkoxycarbonyl and W represents a direct bond, CH₂ or CH₂ CH₂ ; andpharmaceutically acceptable salts thereof.

Preferred are the said compounds of formula Ic and pharmaceuticallyacceptable salts thereof wherein R₉ and R₁₀ represent hydrogen.

Preferred compounds of formula Ic are compounds wherein R₁₁ representscyclohexyl, phenyl, or phenyl monosubstituted as described above.

Also preferred are the compounds of formula II ##STR8## wherein R₂ 'represents hydrogen, halogen, SR₁ ', --NR_(b) '--R₁ ' or NHR₁ '; R₁ 'represents C₃ -C₆ -cycloalkyl, 4-tetrahydropyranyl,4-tetrahydrothiopyranyl, 4-tetrahydropyranyllower alkyl,4-tetrahydrothiopyranyl-lower alkyl, adamantyl-lower alkyl,cyclohexenyl-lower alkyl, C₃ -C₆ -cycloalkyl-lower alkyl, aryl oraryl-lower alkyl in which aryl represents thienyl, pyridyl, phenyl orphenyl substituted by one or two of halogen, trifluoromethyl, loweralkoxy, lower alkyl or by a substituent --W--Z in which W represents adirect bond, lower alkylene or oxy-lower alkylene, and Z representscyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-loweralkylcarbamoyl; or R₁ ' represents a substituent of the formula B'##STR9## in which A' represents a direct bond, methylene, oxy or thio, prepresents zero, one or two, and R_(a) ' represents hydrogen, loweralkyl, lower alkoxy or halogen; R₃ ' represents hydrogen or hydroxy;R_(b) ' represents lower alkyl; and R₆ ' represents lower alkyl, C₃ -C₆-cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable prodrugester derivatives thereof in which free hydroxy groups are esterified inform of a pharmaceutically acceptable ester; and pharmaceuticallyacceptable salts thereof.

Preferred are the compounds of formula II above wherein R₂ ' representschloro, NR_(b) '-R₁ ', or NHR₁ '; R_(a) ' represents hydrogen; R₃ 'represents hydroxy; R₆ ' represents lower alkyl, C₃ -C₆ -cycloalkyl orhydroxy-lower alkyl; and R₁ ', R_(b) ', p and A' have meaning as definedabove; pharmaceutically acceptable prodrug ester derivatives thereof inwhich free hydroxy groups are esterified in form of a pharmaceuticallyacceptable ester; and pharmaceutically acceptable salts thereof.

Further preferred are the compounds of formula IIa ##STR10## wherein R₂' represents NH(CH₂)_(n) --(C₅ or C₆)-cycloalkyl, NR_(b) '--(CH₂)_(n)--(C₅ or C₆)-cycloalkyl, NH(CH₂)_(n) --Ar or NR_(b) '--(CH₂)_(n) Ar inwhich n represents zero or the integer 1,2 or 3, R_(b) ' represents C₁-C₃ -alkyl, and Ar represents 2-, 3- or 4-pyridyl, phenyl-or phenylsubstituted by one or two of halogen, trifluoromethyl, lower alkoxy,lower alkyl or by a substituent --W--Z in which W represents a directbond, straight chain C₁ -C₄ -alkylene or oxy-C₁ -C₃ -alkylene, and Zrepresents cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- orN,N-di-lower alkylcarbamoyl; R₆ ' represents C₁ -C₄ -alkyl, cyclopropylor hydroxy-C₂ -C₄ - alkyl; R₇ and R₈ represent hydrogen, lower alkanoyl,lower alkoxy-lower alkanoyl, aroyl, carbamoyl, mono- or di-loweralkylcarbamoyl; and pharmaceutically acceptable salts thereof.

Particular embodiments thereof relate to the said compounds of formulaIIa wherein n represents the integer 2 and wherein n represents zero.

Particularly preferred are said compounds of formula IIa wherein R₂ 'represents NHCH₂ CH₂ -cyclohexyl, N(CH₃)--CH₂ CH₂ -cyclohexyl,N(CH₃)--CH₂ CH₂ Ar or NHCH₂ CH₂ Ar in which Ar represents 2- or 3-pyridyl, phenyl or phenyl monosubstituted by a substituent --CH₂ CH₂ --Zin which Z represents cyano, carboxy, lower alkoxycarbonyl, carbamoyl,N-mono- or N,N-di-lower alkylcarbamoyl; R₆ ' represents ethyl orhydroxyethyl; R₇ and R₈ represent hydrogen, lower alkanoyl or loweralkoxy-C₂ -C₄ -alkanoyl; and pharmaceutically acceptable salts thereof.

Most preferred are the said compounds of formula IIa wherein R₂ 'represents 2-cyclohexylethylamino, 2-phenylethylamino,2-(p-carboxyethyl-phenyl)-ethylamino or 2-(2-pyridyl)-ethylamino; R₆ 'represents ethyl; R₇ and R₈ represent hydrogen; and pharmaceuticallyacceptable salts thereof.

A particular preferred embodiment of the invention is also representedby the compounds of formula IIb ##STR11## wherein R₆ ' represents ethyl;R₇ and R₈ represent hydrogen or lower alkanoyl; R₉ represents hydrogenor methyl; R₁₀ represents hydrogen or methyl; R₁₁ represents1-cyclohexenyl, cyclohexyl or cyclohexyl substituted by lower alkyl,hydroxy, lower alkoxy or by a substituent W--Z in which W represents adirect bond, CH₂ or CH₂ CH₂, and Z represents carboxy or loweralkoxycarbonyl; or R₁₁ represents 2-, 3- or 4-pyridyl, phenyl, or phenylmonosubstituted by halogen, lower alkoxy or W--Z in which Z representscarboxy or lower alkoxycarbonyl, and W represents a direct bond, CH₂ orCH₂ CH_(2;) and pharmaceutically acceptable salts thereof

Preferred are said compounds of formula IIb and pharmaceuticallyacceptable salts thereof wherein R₉ and R₁₀ represent hydrogen.

Another preferred embodiment is represented by the compounds of formulaIIa wherein R₂ ' represents NH--Ar in which Ar represents 2-, 3- or4-pyridyl, phenyl or phenyl monosubstituted by halogen, trifluoromethyl,lower alkoxy, lower alkyl, cyano, carboxy, lower alkoxycarbonyl,carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R₆ ' represents ethylor hydroxyethyl; R₇ and R₈ represent hydrogen, lower alkanoyl or loweralkoxy-lower alkanoyl; and pharmaceutically acceptable salts thereof.

Further preferred are said compounds wherein Ar represents phenyl,phenyl monosubstituted by halogen, lower alkyl, lower alkoxy, carboxy orlower alkoxycarbonyl; R₇ and R₈ represent hydrogen; R₆ ' representsethyl; and pharmaceutically acceptable salts thereof.

The general definitions used herein have the following meaning withinthe scope of the present invention.

The term "lower" referred to above and hereinafter in connection withorganic radicals or compounds respectively defines such with up to andincluding 7, preferably up to and including 4 and advantageously one ortwo carbon atoms.

A lower alkyl group is straight chain or branched and preferablycontains 1 to 4 carbon atoms, and represents for example ethyl, propyl,butyl, and advantageously methyl.

A lower alkoxy group is straight chain or branched and preferablycontains 1 to 4 carbon atoms, and represents for example methoxy,ethoxy, propoxy.

Lower alkylene is straight chain or branched alkylene and preferablycontains 1 to 4 carbon atoms, and represents for example methylene,ethylene

Lower alkenyl represents C₃ -C₇ -alkenyl, advantageously allyl.

Halogen is preferably chloro, but may also be fluoro, bromo or iodo.

Optionally substituted cycloalkyl represents 3 to 7 ring membered, i.e.C₃ -C₇ -cycloalkyl, preferably C₃ -C₆ -cycloalkyl, unsubstituted orsubstituted by hydroxy, lower alkyl or a substituent W--Z in which Wrepresents a direct bond or lower alkylene, and Z represents cyano,carboxy or carboxy derivatized in the form of a pharmaceuticallyacceptable ester or amide.

C₃ -C₆ -cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, preferably cyclopropyl in the group R₆ or R₆ '; preferablycyclopentyl or cyclohexyl when in the group R₂ or R₂ '.

Optionally substituted cycloalkyl-lower alkyl represents preferably(cyclopentyl or cyclohexyl)-C₁ -C₄ -alkyl, advantageously 1- or2-(cyclopentyl or cyclohexyl)-ethyl, propyl or butyl optionallysubstituted as described under optionally substituted cycloalkyl.

Aryl is an optionally substituted carbocyclic or heterocyclic aromaticradical, being preferably phenyl, 1-or 2-naphthyl, or phenyl substitutedby one to three, advantageously 1 or 2, of lower alkyl, lower alkoxy,halogen or trifluoromethyl, or phenyl substituted by a substituent--W--Z in which W represents a direct bond, lower alkylene or oxy-loweralkylene and Z represents cyano, carboxy or carboxy derivatized in theform of a pharmaceutically acceptable ester or amide; or pyridyl; orthienyl; or pyrrolyl; or indolyl.

Aryl-lower alkyl represents preferably straight chain or branchedaryl-C₁ -C₄ -alkyl, e.g. benzyl or 1- or 2-phenyl-(ethyl, propyl orbutyl) each unsubstituted or substituted on phenyl ring as defined underaryl above; or 2-, 3- or 4-pyridylmethyl or 2-(2-, 3- or4-pyridyl)-(ethyl, propyl or butyl); or 1- or 2-naphthylmethyl or 2-(1-or 2-naphthyl)-(ethyl, propyl or butyl).

Hydroxy-lower alkyl represents preferably 2-, 3- or 4-hydroxy-C₂ -C₄-alkyl, advantageously hydroxyethyl.

Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl.

Thienyl represents 2- or 3-thienyl.

Pyrrolyl represents preferably N-pyrrolyl.

Aryl-cycloalkyl represents preferably aryl-C₅ -C₆ -cycloalkyl, forexample 2-phenylcyclohexyl, 2-N-pyrrolylcyclohexyl or2-phenylcyclopropyl.

Bicycloalkyl represents preferably bicycloheptyl or bicycloheptylsubstituted by lower alkyl, particularly unsubstituted or lower alkylsubstituted bicyclo[2,2,1]heptyl, such as bornyl, neobornyl, isobornyl,norbornyl, e.g. 2-norbornyl. The term bornyl is synonymous withbornanyl.

Adamantyl represents preferably 1-adamantyl.

Cycloalkenyl-lower alkyl represents preferably 1-cyclohexenyl-loweralkyl.

Tetrahydropyranyl and tetrahydrothiopyranyl represent preferably4-tetrahydropyranyl and 4-tetrahydrothiopyranyl, respectively.

A bicyclic benzo-fused 5- or 6-membered saturated carbocyclic radicalrepresents preferably 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl, eachoptionally substituted on benzo portion as indicated above for phenylunder aryl.

A bicyclic benzo-fused 5 or 6-membered saturated heterocyclic radicalrepresents preferably 2,3-dihydro-3-benzofuranyl,2,3-dihydro-3-benzothiofuranyl, 3,4-dihydro-2H-[1]-3-benzopyranyl or3,4-dihydro-2H-[1]-3-benzothiopyranyl, each optionally substituted onbenzo portion as indicated above for phenyl under aryl.

A lower alkoxycarbonyl group preferably contains 1-4 carbon atoms in thealkoxy portion and represents for example: methoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.

Lower alkanoyl represents preferably straight chain or branched C₁ -C₄-alkanoyl, e.g. acetyl, isobutyryl, pivaloyl.

Lower alkoxy-lower alkanoyl represents preferably lower alkoxy-C₂ -C₄-alkanoyl, e.g. methoxyacetyl, 3-ethoxypropionyl.

Aroyl represents preferably benzoyl, benzoyl substituted by one to threeof lower alkyl, lower alkoxy, halogen or trifluoromethyl; 2-, 3- or4-pyridylcarbonyl; or 2- or 3-thienylcarbonyl.

Mono- and di-lower alkylcarbamoyl represents for example N-methyl-,N-ethyl-, N,N-dimethyl- and N,N-diethylcarbamoyl.

Carboxy esterified in form of a pharmaceutically acceptable esterrepresents advantageously an ester that may be convertible by solvolysisor under physiological conditions to the free carboxylic acid, e.g.lower alkoxycarbonyl; (amino, mono- or di-lower alkylamino)substitutedlower alkoxycarbonyl; carboxy substituted lower alkoxycarbonyl, e.g.alpha-carboxy-substituted lower alkoxycarbonyl; loweralkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. alpha-loweralkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted loweralkoxycarbonyl, e.g. optionally substituted benzyloxy carbonyl orpyridylmethoxycarbonyl; (hydroxy, lower alkanoyloxy or loweralkoxy)-substituted lower alkoxy carbonyl, e.g.pivaloyloxymethoxycarbonyl; (hydroxy, lower alkanoyloxy or loweralkoxy)-substituted lower alkoxymethoxycarbonyl;bicycloalkoxycarbonyl-substituted lower alkoxycarbonyl, e.g.bicyclo[2,2,1]-heptyloxycarbonyl-substituted lower alkoxycarbonyl,especially bicyclo[2,2,1]-heptyloxycarbonyl-substituted methoxycarbonylsuch as bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; (loweralkyl, lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; loweralkoxycarbonyloxy-lower alkoxycarbonyl, e.g. 1-(methoxy- orethoxycarbonyloxy)-ethoxycarbonyl; aryloxycarbonyl, e.g. phenoxycarbonylor phenoxycarbonyl advantageously substituted at the ortho position bycarboxy or lower alkoxycarbonyl. Preferred are the lower alkyl andpivaloyloxymethyl esters.

Carboxy derivatized in form of a pharmaceutically acceptable amiderepresents preferably carbamoyl, monolower alkylcarbamoyl or di-loweralkylcarbamoyl.

The pharmaceutically acceptable ester derivatives in which one or morefree hydroxy groups are esterified in the form of a pharmaceuticallyacceptable ester are particularly prodrug esters that may be convertibleby solvolysis under physiological conditions to the compounds of formulaI having free hydroxy groups.

Preferred as said prodrug pharmaceutically acceptable esters arestraight chain or branched lower alkanoic acid esters, e.g., the acetic,isobutyric, pivaloic acid esters; lower alkoxy-lower alkanoic acidesters, e.g., the methoxyacetic, 3-ethoxypropionic acid esters;arylcarboxylic acid esters, e.g., the benzoic, nicotinic acid esters;carbamic and mono or di-lower alkylcarbamic acid esters (carbamates),e.g. the mono- or di-ethylcarbamic or N-mono- or di-methylcarbamic acidesters. Most preferred are the lower alkanoic acid and loweralkoxyalkanoic acid esters.

Pharmaceutically acceptable salts are generally acid addition salts,which are preferably such of therapeutically acceptable inorganic ororganic acids, such as strong mineral acids, for example hydrohalic,e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitricacid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic,acetic, propionic, succinic, glycollic, lactic, malic, tartaric,gluconic, citric, maleic, fumaric, pyruvic, phenylacetic, benzoic,4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic,4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid; or ascorbicacid. For compounds having a free carboxy group, salts are also derivedfrom bases, e.g. the alkali metal salts such as the sodium salt, orsalts derived from amines such as tromethamine.

The novel compounds of the invention are active in state of the art invitro and in vivo test systems, indicative of adenosine receptor agonistactivity in mammals.

The adenosine receptor agonists of the invention are useful in mammalsincluding man for the treatment of e.g. cardiovascular disorders,particularly hypertension and thrombosis.

The above-cited properties are demonstrable in in vitro and in vivotests, using advantageously mammals, e.g. rats, dogs, monkeys orisolated organs, tissues and preparations thereof Said compounds can beapplied in vitro in the form of solutions, e.g. preferably aqueoussolutions, and in vivo either enterally or parenterally advantageouslyorally or intravenously, e.g. within gelatin capsules, as starchsuspensions or in aqueous solutions. The dosage in vitro may rangebetween about 10⁻⁵ molar and 10⁻⁹ molar concentrations. The dosage invivo may range between about 0.001 and 25 mg/kg/day, preferably betweenabout 0.0025 and 10 mg/kg/day depending on the compound and the route ofadministration.

Adenosine-2 (A-2) receptor binding properties, indicative of theadenosine-2 receptor agonist activity of the compounds of the inventionare determined in vitro by determining their ability to inhibit thespecific binding of ³ H-5'-N-ethylcarboxamidoadenosine (³ H-NECA), e.g.essentially as described by R. F. Bruns et al, Mol. Pharmacol. 29, 331(1986), in striatal membrane preparations from corpus striatum of maleSprague-Dawley rats. The concentration of a particular compound requiredto displace the specific binding of 4 nM ³ H-NECA is determined in thepresence of 50nM cyclopentyladenosine.

Adenosine 1 (A-1) receptor binding properties of the compounds of theinvention indicative of adenosine1-receptor agonist activity aredetermined, e.g., essentially according to R.F. Bruns et al in Proc.Natl Acad. Sci. U.S.A. 77:5547 (1980), by determining their ability toinhibit the specific binding of ³ H-cyclohexyladenosine (³ H-CHA) in ratbrain membrane preparations from male Sprague-Dawley rats. Theconcentration of a particular compound required to displace the specificbinding of 1nM ³ H-CHA is determined.

Selectivity for the adenosine-2 (A2) receptor can be ascertained bycomparing the relative potency in the two adenosine receptor assays.

Indicative of in vivo adenosine receptor agonist activity, thehypotensive activity of the compounds of the invention as well as theireffect on heart rate can be measured in normotensive or spontaneoushypertensive rats on intravenous or oral administration.

Typically, the blood pressure lowering effect in normotensive rats canbe determined as follows

Adult male rats weighing 300-400g are anesthetized using Inactin (100mg/kg, i.p.). A femoral artery and contralateral vein are cannulated fordirect blood pressure measurement and i.v. drug administration,respectively. Animals are allowed a 15 minute equilibration periodbefore testing Vehicle (1ml/kg, i.v.) is administered over a 30 secondperiod followed by a 0.3 ml saline flush administered over a 30 secondperiod. Changes in diastolic blood pressure are recorded using a Beckmanpolygraph while heart rate is recorded as a derivative of the bloodpressure pulse. The test compound is administered in the same manner asvehicle and a dose response curve is established. Percent changes inheart rate and blood pressure are recorded.

The blood pressure lowering effect in the spontaneous hypertensive ratis determined on oral administration.

The compounds of the invention which are selective as adenosine-2receptor agonists effectively lower blood pressure without anysignificant effect on the heart rate.

Antithrombotic activity can be demonstrated by measuring the inhibitionof collagen induced platelet aggregation.

Illustrative of the invention, the compounds of example 1b, 2a, 6, 7a,7j, and 12a display IC₅₀ values in the adenosine-2-receptor bindingassay in the range of about 5×10⁻⁶ M to 2×10⁻⁸ M; the compounds alsodisplay hypotensive activity in the anesthesized normotensive rat at adose of about 0.0025 to 0.035 mg/Kg i.v. and in the spontaneoushypertensive rat at a dose of about 3 to 10 mg/Kg p.o.

Further illustrative of the invention, the compound of example 7ainhibits collagen-induced platelet aggregation in human plasma with anIC₅₀ of about 1.5×10⁻⁶ M.

The compounds of the invention of formula I and herein-cited derivativesthereof can be prepared using processes which comprise:

a) for compounds of formula I wherein R, R₁, R₂, R₃, R₄ and R₅ havemeaning as defined hereinabove provided that one of R and R₅ representshydroxy, condensing a compound of the formula III ##STR12## wherein R₁and R₂ have meaning as defined above, with a compound of the formula IV##STR13## wherein R₃ and R₄ have meaning as defined above, in thepresence of a strong base, and separating any resulting isomers if sorequired; or

b) for compounds of formula I wherein R, R₁, R₂, R₃, R₄ and R₅ havemeaning as defined hereinabove, condensing a compound of the formula V##STR14## wherein X represents a leaving group; R, R₂, R₃, R₄ and R₅have meaning as just defined above, with a compound of the formula VI

    R.sub.1 --NH.sub.2 (VI)

in which R₁ has meaning as defined above;

c) for compounds of formula I wherein R₂ represents --SR₁ ', --NR_(b) R₁' or --NHR₁ ', condensing a compound of the formula VII ##STR15##wherein R, R₁, R₃, R₄ and R₅ have meaning as defined above, and X'represents a leaving group, with either a compound of the formula

    R.sub.1 '--NH.sub.2 (VIa)

wherein R'₁ has meaning as defined above; or with a compound of theformula

    R.sub.1 '--SH (VIb)

or a reactive alkali metal salt derivative thereof wherein R'₁ hasmeaning as defined above; or with a compound of the formula

    R.sub.1 '--NR.sub.b H                                      (VIc)

wherein R₁ ' and R_(b) have meaning as defined above;

d) for compounds of formula I wherein R₄ represents --CONHR₆ as definedhereinabove, oxidizing a corresponding compound of the formula I whereinR₄ represents hydroxymethyl and wherein other hydroxy groups are inprotected form, and derivatizing the so obtained carboxylic acid to acompound of formula I wherein R₄ represents --CONHR_(6;)

e) for compounds of formula I wherein R₄ represents loweralkylthiomethyl condensing a compound of formula I wherein R₄ representshydroxymethyl with a di-lower alkyl disulfide in the presence of atri-lower alkylphosphine or converting a compound of formula I whereinR₄ represents hydroxymethyl to a reactive esterified derivative thereofand reacting same with a lower alkylmercaptan or a reactive alkali metalsalt derivative thereof;

f) for compounds of formula I wherein R₂ represents --SR₁ ', reacting acompound of the formula VII wherein X' represents --SH and wherein R,R₁, R₃, R₄ and R₅ have meaning as defined above with an electrophilicreagent corresponding to the radical R₁ '; and, as further required inany of the above-cited processes, temporarily protecting any interferingreactive group(s) in the starting materials and then subsequentlyremoving the protecting groups to yield a resulting compound of formulaI; and, if desired, converting a resulting compound of formula I intoanother compound of the invention, and if desired, converting aresulting free compound into a salt or a resulting salt into a freecompound or into another salt, and if required, separating any mixtureof isomers or racemates obtained into the single isomers or racemates,and if required, resolving a racemate into the optical antipodes.

A leaving group in the above processes represents especially halo, forexample chloro, bromo or iodo, aliphatically or aromatically substitutedsulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy(tosyloxy), or aliphatically substituted thio, for example loweralkylthio such as methylthio.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino and hydroxy, are optionally protected byconventional protecting groups that are common in preparative organicchemistry. Protected amino and hydroxy groups are those that can beconverted under mild conditions into free amino and hydroxy groupswithout the molecular framework being destroyed or undesired sidereactions taking place

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in J.F.W. McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London, New York1973, T.W. Greene, and "Protective Groups in Organic Synthesis", Wiley,New York 1984.

For example, a hydroxy group may be protected in the form of esters,e.g. as acyl derivatives such as the lower alkanoyl, benzyloxycarbonylor lower alkoxycarbonyl esters, or such hydroxy group may be protectedin the form of ethers, e.g. as the 2-tetrahydropyranyl, trityl or benzylethers.

Hydroxy groups on adjacent carbon atoms can also be protected e.g. inthe form of ketals or acetals, such as isopropylidene or benzylidenederivatives

In a resulting protected compound of formula I or intermediate, in whichone or more of the functional groups are protected, the protectedfunctional groups, e.g. hydroxy groups, can be liberated in a mannerknown per se, e.g. by means of solvolysis, especially hydrolysis withacid, or by hydrogenolysis.

The preparation of the compounds of the invention according to processa) which involves opening of an epoxide ring is preferably carried outin a polar solvent such as dimethylformamide and at an elevatedtemperature, advantageously at a temperature ranging from 50 to 125° C.The reactive organometallic derivative, e.g. the lithium, sodium orpotassium derivative of the starting material of formula III ispreferably first prepared in situ by reacting a compound of the formulaIII with a corresponding strong base such as sodium, potassium orlithium hydride or amide in a polar anhydrous solvent such asdimethylformamide, advantageously at room temperature.

Process a is preferred for compounds of formula I wherein R₂ representshydrogen or halogen

Starting materials of formula III (adenine and derivatives thereof) canbe prepared according to methods known in the art for the synthesis andderivatization of purines, e.g. as illustrated in Barton and Ellis,Comprehensive Organic Chemistry Vol. 4, pp. 499-518.

Starting materials of formula IV are either known in the art or arepreferably prepared as illustrated below. A more specific embodimentrelates to the compounds of formula IVa, particularly the compounds offormula IVa wherein R₄ represents --CONHR₆ as defined herein. ##STR16##

A cyclopentene derivative VIII wherein R₄ has meaning as defined hereincan be hydroxylated, e.g. with selenium dioxide in organic solvents suchas tetrahydrofuran and dimethoxyethane, preferably at reflux temperatureto give the hydroxy substituted cyclopentene derivative of formula IX.Epoxidation of the cyclopentene derivatives of either formula VIII orIX, e.g. with m-chloroperbenzoic acid in a solvent such asdichloromethane at room temperature, yields a corresponding epoxide offormula IV wherein R₃ represents hydrogen or wherein R₃ representshydroxy (of formula IVa above), respectively.

The epoxidation of the cyclopentene derivatives can also be carried outunder Sharpless epoxidation conditions with t-butyl hydroperoxide,preferably in the presence of vanadium or titanium catalysts such asvanadyl acetylacetonate or titanium tetraisopropoxide. Asymmetricepoxidation for kinetic resolution of the epoxides into the opticallyactive isomers can be similarly carried out in the presence of e.g. adiester of d- or 1-tartaric acid, as described in Pure and AppliedChemistry 55, 589 (1983).

The preparation of the compounds of the invention according to processb) which involves the displacement of a leaving group X (e.g. chloro) ina compound of the formula V by an amine of the formula VI is preferablycarried out at elevated temperature, e.g. at a temperature ranging from75 to 150° C., with an excess of the amine, in the absence or presenceof a solvent, particularly a polar solvent such as methanol ordimethylformamide, or under elevated pressure, or in the presence of abase such as triethylamine.

The starting materials of formula V wherein R₂ represents hydrogen orhalogen can advantageously be prepared by condensing a compound of theformula X ##STR17## wherein X, R and R₂ -R₅ have meaning as defined forcompounds of formula V, optionally in partially protected form, withformic acid or a mixture of formic acid and acetic anhydride, with alower alkylcarboxylic acid ester of a di-lower alkoxymethanol or with atri-lower alkyl orthoformate, and as required, liberating any protectedhydroxy groups.

The condensation is preferably carried out by reacting a compound offormula X with a tri-lower alkyl orthoformate, such as triethylorthoformate in a polar solvent such as dimethylacetamide in thepresence of an acid such as concentrated hydrochloric acid, preferablyat room temperature.

The intermediates of formula X can be prepared by condensing e.g. acompound of the formula ##STR18## wherein R₂ has meaning as defined forformula V, with a compound of the formula ##STR19## wherein R, R₃, R₄and R₅ have meaning as defined above, e.g. according to generalprocedures described in J. Am. Chem. Soc. 91, 3075 (1969) and J. Org.Chem. 45, 531 (1980), preferably in the presence of a base such astriethylamine.

The compounds of formula XI and XII can in turn be prepared according toprocedures known in the art, e.g. the compounds of formula XII can beprepared according to Tetrahedron Letters 22, 2331 (1981) or J. Org.Chem. 45, 531 (1980).

The starting materials of formula V wherein R₂ represents --SR₁ ',--NRbR₁ ' or --NHR₁ ', and X represents a leaving group, can be preparede g. by reacting a compound of formula V wherein X represents hydroxy(or as the oxo tautomer thereof) with a halogenating agent such asphosphorus oxychloride.

The intermediates of formula V wherein X represents hydroxy can in turnbe prepared by first converting a compound of formula V, or a protectedderivative thereof, wherein X and R₂ both represent chloro to a compoundof formula V wherein X represents hydroxy and R₂ represents chloro byhydrolysis with acid and subsequently converting said intermediate,using methodology as described e.g. for process (b) and (f), to acompound of formula V wherein X represents hydroxy and R₂ represents--SR₁ ', --NR_(b) R₁ ' or --NHR₁ '.

The preparation of the compounds of the invention according to processc) which involves the displacement of the leaving group X' (e.g. chloro)in a compound of formula VII by an amine of the formula VIa or VIc iscarried out essentially as described above under process b). Thedisplacement by a mercaptan of the formula VIb is carried out preferablyin the presence of a strong base, e.g. an alkali metal hydroxide.

The starting materials of formula VI, VIa, VIb and VIc are either knownor are prepared using methods known in the art, and as described herein.

The starting materials of formula VII can be prepared e.g. essentiallyas described under process a), by reacting the correspondinglysubstituted purine derivatives with an epoxide of the formula IV.

The preparation of compounds of the invention wherein R₄ represents--CONHR₆ according to process d) can be carried out by oxidizing thecorresponding compounds wherein R₄ represents hydroxymethyl, the otherhydroxy groups in the molecule being in a protected form, with e.g.potassium permanganate, and converting the so obtained carboxylic acidto a reactive derivative, e.g. the acid chloride, and condensing saidcarboxylic acid chloride with an amine of the formula R₆ --NH₂, underconditions well known in the art.

The preparation of compounds of the invention wherein R₄ representslower alkylthiomethyl according to process e) can be carried out byconverting the corresponding compounds wherein R₄ representshydroxymethyl, the other hydroxy groups being preferably in a protectedform, to e.g. the chloro derivative by treatment with e.g. thionylchloride in hexamethylphosphorus triamide (HMPT) and reacting saidchloro derivative with e.g. the lithium salt of a lower alkyl mercaptan,for example lithium methylmercaptide, in a polar solvent such astetrahydrofuran.

Alternately, a compound wherein R₄ is hydroxymethyl is treated with adi-lower alkyl disulfide in the presence of e.g. tributylphosphine atelevated temperature in a polar solvent such as dimethylformamide.

The preparation according to process (f) of compounds of the inventionwherein R₂ represents --SR₁ ' is carried out according to procedureswell-known in the art, e.g. by displacement of a leaving group.

The starting materials of formula VII wherein X' represents SH can beprepared e.g. by reacting a compound of formula VII wherein X'represents a leaving group, e.g. chloro, with an alkali metal hydrogensulfide such as sodium hydrogen sulfide.

The starting compounds for processes d) and e) can be prepared e.g. asdescribed in process a).

The compounds of the invention or intermediates leading thereto can beconverted into other compounds of the invention or correspondingintermediates using chemical methodology known in the art and asillustrated herein.

The compounds of formula I wherein R₂ represents halogen, e.g. chloro,can be converted according to process c) as described above to compoundsof formula I wherein R₂ represents --NHR'₁.

The conversion of compounds of formula I containing free hydroxy groupsto ester derivatives thereof may be carried out by condensation with acorresponding carboxylic acid, advantageously as a reactive functionalderivative thereof, according to acylation (esterification) procedureswell-known in the art.

The compounds of formula I wherein R₄ represents hydroxymethyl (aminoand any other hydroxy groups in the molecule being in protected form)can be converted to compounds of formula I wherein R₄ represents loweralkoxymethyl by condensation with an equivalent amount of e.g. a loweralkyl halide such as a lower alkyl iodide in the presence of anequivalent amount of a strong base, such as sodium hydride in anon-aqueous solvent, such as dimethylformamide.

A compound of formula I containing a primary amino group (e.g. whereinNHR₁ or NHR₁ '=NH₂) may be converted to a compound of formula I whereinNHR₁ or NHR₁ ' represents a secondary amine, e.g. wherein R₁ in or R₁ 'represents lower alkyl, by treatment with a reactive derivative of thealcohol corresponding to R₁, or R₁ ' e.g. with a lower alkyl halide suchas a lower alkyl iodide, according to methodology well-known in the artfor alkylation of amines.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures preferably nearthe boiling point for the solvents used, at atmospheric orsuperatmospheric pressure

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed under the reaction conditions, or inwhich the reaction components are used in the form of their salts oroptically pure antipodes. Whenever desirable, the above processes arecarried out after first suitably protecting any potentially interferingreactive functional groups, as illustrated herein.

Advantageously, those starting materials should be used in saidreactions that lead to the formation of those compounds indicated aboveas being preferred.

The invention also relates to novel starting materials and processes fortheir manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers, forexample, as diastereomers, as optical isomers (antipodes), as racemates,or as mixtures thereof.

In case diastereomeric mixtures of the above compounds or intermediatesare obtained, these can be separated into the single racemic oroptically active isomers by methods in themselves known, e.g. byfractional distillation, crystallization or chromatography.

The racemic products of formula I or basic intermediates can be resolvedinto the optical antipodes, for example, by separation of diastereomericsalts thereof, e.g., by the fractional crystallization of d- or1-(tartrate, dibenzoyltartrate, mandelate or camphorsulfonate) salts.

Advantageously, the more active of the antipodes of the compounds ofthis invention is isolated.

Finally, the compounds of the invention are either obtained in the freeform, or as a salt thereof. For example, any resulting free base can beconverted into a corresponding acid addition salt, preferably with theuse of a pharmaceutically acceptable acid or anion exchange preparation,or resulting salts can be converted into the corresponding free bases,for example, with the use of a stronger base, such as a metal orammonium hydroxide, or any basic salt, e.g., an alkali metal hydroxideor carbonate, or a cation exchange preparation. These or other salts,for example, the picrates, can also be used for purification of thebases obtained; the bases are then first converted into salts. In viewof the close relationship between the free compounds and the compoundsin the form of their salts, whenever a compound is referred to in thiscontext, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances.

The compounds, including their salts, may also be obtained in the formof their hydrates, or include other solvents used for thecrystallization.

The present invention also relates to the use of the compounds of theinvention for the preparation of pharmaceutical compositions, especiallypharmaceutical compositions having selective adenosine (particularlyadenosine-2) receptor stimulating (agonist) activity which can be usedfor the treatment of e.g. cardiovascular conditions, such ashypertension, thrombosis and atherosclerosis.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, for the treatment of diseasesresponsive to adenosine (particularly adenosine-2) receptor stimulationas given above, such as hypertension, comprising an effectiveadenosine-2 receptor stimulating amount of a compound of the invention,alone or in combination with one or more pharmaceutically acceptablecarriers.

The pharmacologically active compounds of the invention are incorporatedinto pharmaceutical compositions comprising an effective amount thereofin conjunction or admixture with excipients or carriers suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salts and/or polyethylene glycol; for tablets alsoc) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired, d) disintegrants, e.g. starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbents, colorants, flavors and sweeteners. Injectable compositionsare preferably aqueous isotonic solutions or suspensions, andsuppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, the compositions may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50 %,of the active ingredient.

Suitable formulations for transdermal application include an effectiveamount of a compound of the invention with carrier Advantageous carriersinclude absorbable pharmacologically acceptable solvents to assistpassage through the skin of the host. Characteristically, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound, optionally with carriers, optionallya rate controlling barrier to deliver the compound to the skin of thehost at a controlled and predetermined rate over a prolonged period oftime, and means to secure the device to the skin.

The present invention also relates to the use of compounds of theinvention having adenosine receptor stimulating properties andpharmaceutical compositions comprising said compounds for the treatmentin mammals of disorders responsive to selective adenosine receptorstimulation, particularly cardiovascular conditions (e.g. hypertensionand thrombosis).

One aspect relates advantageously to the method of treatment ofcardiovascular disorders in mammals, e.g. such responsive to adenosine(particularly adenosine-2) receptor stimulation, for examplehypertension, using an effective amount of a compound of the invention,preferably in the form of above-cited pharmaceutical compositions.

The dosage of active compound administered is dependent on the speciesof warm-blooded animal (mammal), the body weight, age and individualcondition, and on the form of administration.

A unit dosage for a mammal of about 50 to 70 kg may contain betweenabout 1 and 50 mg of the active ingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100 mmHg. The structure of final products, intermediates and startingmaterials is confirmed by analytical methods, e.g. microanalysis andspectroscopic characteristics (e.g. MS, IR, NMR).

The numbering of the positions of the adenine and or purine rings is asconventionally used in the art (e.g. Merck Index, tenth edition).

Unless otherwise indicated the final products are preferably isolated asthe free base by crystallization from a mixture of an alcohol (methanol,ethanol or isopropanol) and ethyl ether.

EXAMPLE 1

To a suspension of 1.2 g sodium hydride (60%, washed with dry ether) in20 ml of dry dimethylformamide is added 2.58 g adenine. After 10 minutesstirring at room temperature the resulting mixture is treated with asolution of 4.9 g2-alpha-hydroxy-3-alpha,4-alpha-epoxy-cyclopentane-1-β-N-ethylcarboxamidein 30 ml of dry dimethylformamide, heated at 105° for 18 hours, thencooled to room temperature. The reaction mixture is quenched with waterand concentrated under vacuo. The crude product is purified by reversephase chromatography using 120 g of reverse phase octadecylsilane(C₁₈)-bonded silica gel to yield a)2-alpha-4-alpha-dihydroxy-3β-(9-adenyl)-cyclopentane-1β-N-ethylcarboxamide,m.p. 250-253°, and b)2-alpha,3-alpha-dihydroxy-4β-(9-adenyl)-cyclopentane-1-β-N-ethylcarboxamide(the compound of formula IIa wherein R₂ ', R₇ and R₈ are hydrogen and R₆' is ethyl) which is recrystallized from methanol, m.p. 208.5-209° ;NMR(CD₃ OD): 8.36 (1H,s), 8.18(1H,s), 4.5(1H,dd) 4.28(12H,dd).

The starting material is prepared as follows

To a mixture of 750 ml of dry tetrahydrofuran and 375 ml of drydimethoxyethane is added 15 g 3-cyclopentene-1-N-ethylcarboxamide,followed by 12 g selenium dioxide at room temperature. After thereaction is heated to 70° with mechanical stirring overnight and cooledto room temperature, the resulting solution is filtered through Celite®.The filtrate is concentrated under vacuo and the residue ischromatographed on 400 g silica gel using 4% MeOH in ethyl acetate aseluent to give 2-alpha-hydroxy3-cyclopentene-1-β-N-ethylcarboxamide,m.p. 48-50° .

A solution of 4.6 g2-alpha-hydroxy-3-cyclopentene-1-β-N-ethylcarboxamide, 10.23 gm-chloroperbenzoic acid and 70 ml of dichloromethane is stirred at roomtemperature for 2 hours. The solvent is removed under reduced pressureand the residue is partitioned between ether and water. The aqueouslayer is concentrated in vacuo to obtain2-alpha-hydroxy-3-alpha,4-alpha-epoxycyclopentane-1-β-N-ethylcarboxamide,m.p. 83-85°.

Similarly prepared are:

c)2-alpha,3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1-.beta.-N-ethylcarboxamide,m.p. 233-237°; NMR(CD₃ OD): 8.34 (1H,s), 4.43 (1H,dd), 4.25(1H,t);

d) 3-alpha-hydroxy-4-β-(9-adenyl)-cyclopentane-1-β-N-ethylcarboxamide,m.p. 282-285°; NMR(CD₃ OD): 8.17 (1H,s), 8.15 (1H,s), 4.7 (1H,s):

e) 2-alpha,3-alpha-dihydroxy-4-β-(9-adenyl)-cyclopentane-1-β-N-cyclopropylcarboxamide,m.p. 218-220°; NMR(CD₃ OD): 8.20(1H,s), 4.47(1H,dd), 4.25(1H,t).

f)2-alpha,4-alpha-dihydroxy-3β-(9-adenyl)-cyclopentane-1β-N-cyclopropylcarboxamide,m.p. above 250°.

g)3-alpha-hydroxy-4β-(2-chloro-9-adenyl)cyclopentane-1-β-N-ethylcarboxamide,m.p. 197-200°; NMR(CD₃ OD): 8.1 (1H,s), 4.13 (1H,q).

The starting material for compounds d and g,3-alpha-4-alpha-epoxy-cyclopentane-1-β-N-ethylcarboxamide, is preparedby epoxidation of 3-cyclopentene-1-N-ethylcarboxamide withm-chloroperbenzoic acid followed by chromatographic purification onsilica gel (using 2% methanol in ethyl acetate as eluent).

EXAMPLE 2

a) A stirred mixture of 58 mg of2-alpha,3-alphadihydroxy-4β-[9-(2-chloroadenyl)]-cyclopentane-1-β-N-ethyl-carboxamide and 1.5 ml of freshly distilled2-phenylethylamine is heated to 130° for 14 hours and cooled to roomtemperature. Excess 2-phenylethylamine is removed under vacuo and theresidue is triturated with ether. The solid which is obtained afterfiltration is recrystallized from methanol to give2-alpha,3-alpha-dihydroxy-4β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane1-β-N-ethylcarboxamide,the compound of formula IIa wherein R₂ ' is 2-phenylethylamino, R₆ ' isethyl, R₇ and R₈ are hydrogen; m.p. 234-236°; NMR (CD₃ OD): 7.9 (1H,s),4.46 (1H,t) 4.33 (1H,t). Further recrystalization gives m.p. 244-245°.

Similarly prepared are:

b)3-alpha-hydroxy-4β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1-.beta.-N-ethylcarboxamide,m.p. 220-224°; NMR (CD₃ OD): 7.73 (1H,s), 3.22 (2H,q), 2.91 (2H,t), 2.48(2H,t);

c)2-alpha,4-alpha-dihydroxy-3β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1-β-N-ethylcarboxamide, m.p. 224-226°; NMR(CD₃ OD): 7.8 (1H,s), 4.25 (1H,dd);

d)2-alpha,3-alpha-dihydroxy-4β-[2-(2-pyridylethylamino)-9-adenyl]-cyclopentane-1-β-N-ethylcarboxamide; NMR (CD₃ OD): 7.93 (1H,s), 4.47 (1H,t), 4.37 (1H,t);m.p. 230-232°.

EXAMPLE 3

To a suspension of 241 mg sodium hydride (60%, washed with dry ether) in8 ml dry dimethylformamide is added 932 mg of 2-chloroadenine. After 10minutes stirring at room temperature, the resulting mixture is treatedwith 800 mg of1-β-hydroxymethyl-2-alpha-hydroxy-3-alpha,4-alpha-epoxycyclopentane in 5ml dry dimethylformamide and heated at 105°for 18 hours, then cooled toroom temperature. The reaction mixture is quenched with water andconcentrated under vacuo. The crude product is chromatographed on 100 greverse phase octadecylsilane (C₁₈)-bonded silica gel (eluent, 5%methanol in water) to give a) 2-alpha,4-alpha-dihydroxy-1β-hydroxymethyl-3β(2-chloro-9-adenyl)-cyclopentane,m.p. 252-254°, and b) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentane,m.p. 236-238°; NMR (CD₃ OD): 8.17 (1H,s), 4.5 (1H,dd), 4.04 (1H,dd).

The starting material is prepared as follows:

A solution of 4.15 g of 1-hydroxymethyl-3-cyclopentene in 500 ml of drytetrahydrofuran and 250 ml of dimethoxyethane is treated with 4.15 gselenium dioxide at room temperature. The resulting mixture is heated at70° for 18 hours, then cooled to room temperature and filtered throughCelite®. The filtrate is concentrated under vacuo and the residue ischromatographed on 100 g of silica gel (eluent, 4% methanol in ethylacetate) to give trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene.

A solution of 818 mg trans-1-hydroxymethyl-2-hydroxy-3-cyclopentene, 2.2g m-chloroperbenzoic acid and 40 ml of dichloromethane is stirred atroom temperature for 80 minutes. The solvent is removed under reducedpressure and residue is partitioned between ether and water. The aqueouslayer is concentrated in vacuo to obtain1-β-hydroxymethyl-2-alpha-hydroxy-3-alpha,4-alpha-epoxy-cyclopentane.

EXAMPLE 4

A suspension of 40 mg of sodium hydride (60%, washed with ether) in 3 mlof dimethylformamide is treated with 200 mg of2-(2-phenylethylamino)adenine at room temperature. Stirring is continuedat room temperature until the reaction mixture becomes homogeneous. Thereaction mixture is then treated with 160 mg2-alpha-hydroxy-3-alpha,4-alpha-epoxy-cyclopentane-1β-N-ethylcarboxamide. The resulting solution is heated at 100° for 14hours. The reaction mixture is then cooled to room temperature quenchedwith water and the solvent is removed under vacuum. The crude productmixture is first chromatographed in silica gel eluting with 10% MeOH/CH₂Cl₂ to 15% MeOH/CH₂ Cl₂. The resulting product is then chromatographedon reverse phase octadecylsilane (C₁₈)-bonded silica gel eluting with upto 50% methanol in water; a mixture of isomers, 2-alpha,3-alpha-dihydroxy-4-β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane1-β-N-ethylcarboxamide of example 2a and 2-alpha,4-alpha-dihydroxy-3β-[2-(2-phenylethylamino)-9-adenyl]-cyclo -pentane-1β-N-ethylcarboxamideis obtained.

The starting material 2-(2-phenylethylamino)-adenine is prepared byreacting 2-chloroadenine with excess 2-phenylethylamine at about 140°.

EXAMPLE 5

a) To a stirring solution of 2.7 g of4β-(5-amino-6-chloro-4-pyrimidinylamino)-2-alpha,3-alpha-dimethyl-methylenedioxy-cyclopentane-1β-N-ethylcarboxamide in 40 ml oftriethyl orthoformate is added 0.7 ml of concentrated HCl. The solutionis stirred at room temperature for 24 hours. After removal of thesolvent,4β-(6-chloro-9-purinyl)-2-alpha,3-alpha-dimethylmethylenedioxy-cyclo-pentane-1β-N-ethylcarboxamide is obtained as an oil, which is used inthe next step without further purification.

A solution of 2.2 g of4β-(6-chloropurin-9-yl)2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide in 30 ml of saturated methanolic ammonia isheated overnight in a sealed tube. After removing the solvent, theresidue is heated at 55° in 15 ml 1N HCl for 1.75 hours. The solvent isremoved under vacuum to give an amorphous solid.

Chromatography on a flash silica gel column eluting using a methanol:dichloromethane gradient gives4β-(9-adenyl)-2-alpha,3-alpha-dihydroxycyclopentane1β-N-ethylcarboxamide,identical to the compound of example 1b.

The starting material is prepared as follows:

A mixture of 10.5g of5,6-dimethylmethylenedioxy-2azabicyclo[2.2.1]-heptan-3-one and 50 ml ofethylamine is heated at 140° in a steel bomb overnight. After removal ofthe solvent, the residue is purified by column chromatography (silicagel) using a gradient of dichloro-methane: methanol as eluent to give4β-amino-2-alpha,-3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide.

To a solution of 5.3g of4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide in 70 ml of n-butanol is added 7.5 g of5-amino-4,6-dichloropyrimidine followed by 9.2 ml of triethylamine.After the reaction is heated for 24 hours at 150°, the solvent isremoved in vacuo. The residue is partitioned between ethyl acetate and asaturated sodium bicarbonate solution. The organic layer is dried oversodium sulfate and concentrated to dryness. The crude solid ischromatographed on a silica gel column eluting using a hexane: ethylacetate gradient to yield4β-(5-amino-6-chloro-4-pyrimidinylamino)-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide.

b) Similarly prepared is2-alpha,3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1-.beta.-N-ethylcarboxamide, the compound of example 1c.

The starting material is prepared as follows:

To a solution of 614 mg 5-amino-2,4,6-trichloropyrimidine and 813 mg of4-β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamidein 15 ml of n-butanol is added 1 ml of dry triethylamine; the resultingmixture is heated at reflux for 15 hours and cooled to room temperature.All the volatiles are evaporated and the residue is partitioned betweendichloromethane and water. The organic layer is dried over magnesiumsulfate and concentrated to an oil. The crude product is chromatographedon 100 g silica gel using 1:1 hexane and ethyl acetate as eluent to give4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide as an amorphous solid.

EXAMPLE 6

A stirred mixture of 26 mg2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentane (Example 3) and 0.3 ml freshly distilled2-phenylethylamine is heated at 130° for 14 hours and cooled to roomtemperature. Excess 2-phenylethylamine is removed under vacuo and theresidue is triturated with ether. The solid which is obtained afterfiltration is purified by flash column chromatography using a reversephase octadecylsilane (C₁₈)-bonded silica gel packing and eluting withMeOH: water (5:3 to 1:1). The resulting product is then crystallizedfrom ethanol/ether to give2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane,m.p. 118-120°; NMR (CD₃ OD): 7.73 (1H,s), 7.18 (5H,m), 2.85(2H,t).

EXAMPLE 7

The following compounds of formula II wherein R₃ ' represents hydroxycan be prepared substantially according to the general proceduresdescribed herein.

    __________________________________________________________________________     ##STR20##                            (II)                                    Compound                                                                             R.sub.2 '           R.sub.6 '                                                                             m.p.                                       __________________________________________________________________________    (a)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4CH.sub.2 CH.sub.2 COOH                                       CH.sub.2 CH.sub.3                                                                     235-237°                                   (HCl salt)                                                             (b)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4OCH.sub.2 COOH                                               CH.sub.2 CH.sub.3                                  (c)    3,4-dihydro-5-methoxy-2H[1]                                                                       CH.sub.2 CH.sub.3                                         benzothio-pyran-3-ylamino                                              (d)    2-indanylamino      CH.sub.2 CH.sub.3                                  (e)    1,2,3,4-tetrahydro-2-naphthyl-                                                                    CH.sub.2 CH.sub.3                                         amino                                                                  (f)    3,4-dihydro-2H-[1]-benzo-                                                                         CH.sub.2 CH.sub.3                                         pyran-3-ylamino                                                        (g)    H                   CH.sub.2 CH.sub. 2 OH                              (h)    SCH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.2 CH.sub.3                                  (i)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4OCH.sub.2 CH.sub.2 COOH                                      CH.sub.2 CH.sub.3                                  (j)    2-cyclohexylethylamino                                                                            CH.sub.2 CH.sub.3                                                                     228-232°                            (k)    1-naphthylmethylamino                                                                             CH.sub.2 CH.sub.3                                                                     223-225°                            (l)    N-methyl-2-phenethylamino                                                                         CH.sub.2 CH.sub.3                                                                     194-196°                            (m)    2-(p-methoxyphenyl)-1-methyl-                                                                     CH.sub.2 CH.sub.3                                         ethylamino                                                             (n)    2-phenylpropylamino CH.sub.2 CH.sub.3                                                                     210-212°                            (o)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4CH.sub.2 COOH                                                CH.sub.2 CH.sub.3                                  (p)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4CH.sub.2 CON(CH.sub.3).sub.2                                 CH.sub.2 CH.sub.3                                  (q)    NH(CH.sub.2).sub.2 -p-C.sub.6 H.sub.4 Cl                                                          CH.sub.2 CH.sub.3                                  (r)    NHCH.sub.2 CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.3                                                                     173-176°                            (s)    2-cyclopentylethylamino                                                                           CH.sub.2 CH.sub.3                                  __________________________________________________________________________

Compound (a) can be advantageously prepared as follows:

p-Bromophenylacetonitrile is first condensed with t-butyl acrylate underconditons of the palladium acetate catalyzed Heck reaction. Theresulting acrylate is hydrogenated with palladium on charcoal catalystfollowed by reduction (of the cyano group) with sodium borohydride inthe presence of cobalt(II) chloride to yield t-butylp-(2-aminoethyl)-phenylpropionate. Condensation with2-alpha,3-alpha-dihydroxy-4β-[9-(2-chloroadenyl)]-cyclopentane-1.beta.-N-ethylcarboxamideyields the t-butyl ester of compound (a) which is hydrolyzed to compound(a) with aqueous hydrochloric acid.

Compound (b) is similarly prepared. The starting material forcondensation with the 9-(2-chloroadenyl)-cyclopentane derivative isprepared by condensation of p-hydroxyphenylacetonitrile with t-butylbromoacetate in the presence of potassium carbonate.

The starting material for compound (c) is prepared as follows: To acooled mixture of 30.6 g of m-methoxybenzenethiol, 54.4 g of 45%potassium hydroxide in 100 ml of dimethylsulfoxide is added 36.0 g ofalpha(bromomethyl)-acrylic acid in 25 ml of dimethylsulfoxide at such arate as to maintain the reaction temperature at 50-55°. After 1 hour thereaction mixture is diluted with water and washed with ether. Afteracidification, the product is extracted with ether, the organic layer isdried over magnesium sulfate and the solvent is removed in vacuo toafford alpha-(3-methoxybenzenethiomethyl)acrylic acid. This material isdissolved in 570 ml of o-dichlorobenzene and 7.2 g of triethylamine andheated to 200° for 5 hours. After cooling, the products are extractedwith sodium bicarbonate solution, the aqueous layer is acidified and theproducts extracted with ether. After drying over magnesium sulfate, thesolvent is removed in vacuo to afford a mixture of3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-carboxylic acid and3,4-dihydro-7-methoxy-2H-[1]-benzothiopyran-3-carboxylic acid.

This mixture of acids is dissolved in 500 ml of t-butyl alcohol andtreated with 17 g of triethylamine and 36 ml of diphenylphosphorylazide. After 5 hours reflux, the solvent is removed in vacuo and theresidue is dissolved in ether and washed with 1N sodium hydroxide and 1Nhydrochloric acid. After drying over magnesium sulfate, the solvent isremoved in vacuo and the residue is chromatographed on silica gel (1kg)with ether/hexane (1:4) as the eluent to afford in successionN-t-butoxycarbonyl-3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran3-amineandN-t-butoxycarbonyl-3,4-dihydro-7-methoxy-2H-[1]-benzothiopyran-3-amine.

A solution of 10 g ofN-t-butoxycarbonyl-3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-aminein 30 ml of trifluoroacetic acid is kept at room temperature for 1 hour.The solvent is removed in vacuo, the residue is treated with 1N NaOH andthe product is extracted with ether. After drying over magnesiumsulfate, the solvent is removed in vacuo to afford3,4-dihydro-5-methoxy-2H[1]-benzothiopyran-3-amine as an oil.

The starting material for compound (o) is prepared as follows:

A mixture of 20 g of p-bromophenylacetic acid, 30 ml of ether, 1 ml ofsulfuric acid and 35 ml of isobutylene is shaken in a sealed bottle for24 hours. The reaction mixture is diluted with ether and washed withsodium hydroxide solution. After drying over magnesium sulfate the etheris removed in vacuo to afford the t-butyl ester as an oil. A mixture of9.6 g of this material is refluxed with a mixture of 6.1 g ofN-vinylphthalimide, 160 mg of palladium acetate, 800 mg oftri-o-tolylphosphine, 10 ml of acetonitrile and 8 mldiisopropylethylamine for 24 hours. The reaction is diluted with water,the resulting precipitate is collected and recrystallized frommethanol/methylene chloride. The resulting solid is hydrogenated at 4atmospheres pressure over 2 g of 10% palladium on carbon catalyst in 100ml of ethanol and 100 ml of tetrahydrofuran for 16 hours at roomtemperature. After removal of the solvent in vacuo the residue is heatedat reflux with 10 ml of hydrazine hydrate and 20 ml of ethanol for 2hours. The reaction is diluted with ether and washed with 5% potassiumhydroxide solution. The ether is dried over magnesium sulfate solutionand the solvent is removed in vacuo. The residue is chromatagraphed onsilica gel, with 5% ammonia saturated methanol in methylene chloride asthe eluent, to afford p-(t-butoxycarbonylmethyl)-2-phenethylamine as anoil.

The starting material for compound p is prepared as follows:

A mixture of 6 g of p-bromophenylacetic acid in 100 ml of methylenechloride and 5 ml of oxalyl chloride is stirred at room temperature for16 hours. After removal of the solvent in vacuo the residue is dissolvedin methylene chloride and treated with excess dimethylamine at roomtemperature. After 1 hour the reaction mixture is washed with water, theorganic layer is dried over magnesium sulfate and the solvent is removedin vacuo to afford p-bromo-N,N-dimethyl-phenylacetamide as an oil, whichis converted to p-(dimethylaminocarbonylmethyl)-2-phenethylamine asdescribed for the starting material above.

EXAMPLE 8

2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-cyclopentane (480 mg) is treated with 8.0 ml triethyl orthoformate and0.1 ml concentrated HCl, and the reaction mixture is stirred at roomtemperature for one hour. The reaction mixture is then concentratedunder vacuum and the residual oil is dissolved in 20 ml of saturatedmethanolic ammonia, the solution is placed in a sealed tube and heatedat 60° for 12-16 hours. The solvent is removed under vacuum and theresidue heated with 30 ml 1N HCl at 60° for 2 hours. The solvent isremoved under vacuum and the crude product is separated by flashchromatography on a reverse phase octadecylsilane (C₁₈)-bonded silicagel packing, eluting first with water, followed by 5%, 10% and 20%methanol in water to yield2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride (see example 3); NMR (CD₃ OD): 8.2 (1H,s), 4.50 (1H,dd)4.03 (1H,dd), 3.70 (2H,m), 2.46 (1H,m), 2.25 (1H,m), 1.90 (1H,m).

The starting material is prepared as follows:

A mixture of 5.2 g of methyl 4β-amino-2-alpha,3-alpha-dihydroxycyclopentane-1β-carboxylate (Tetrahedron Letters 1981,2331), 3.4 g of 5-amino-2,4,6-trichloropyrimidine and 5.2 ml oftriethylamine in 60 ml n-butanol is heated to reflux under nitrogenatmosphere for 16 hours. The reaction mixture is cooled to roomtemperature and the solvent removed under vacuum. The residue ispartitioned between ethyl acetate and water. The organic solution isextracted with saturated sodium chloride solution dried over magnesiumsulfate and evaporated to dryness. The crude product is purified byflash column chromatography on silica gel, eluting with ethyl acetateand then 10% methanol in ethyl acetate to yield methyl2-alpha,3-alpha-dihydroxy-4-β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-cyclopentane-1β-carboxylateas a white solid. NMR (CD₃ OD): 4.43 (1H,q), 4.25 (1H,t), 3.95 (1H,t),3.72 (3H,s), 2.94 (1H,m), 2.60 (1H,m), 1.70 (1H,m).

Calcium chloride (466 mg) and sodium borohydride (320 mg) are combinedin 30 ml tetrahydrofuran at room temperature. The reaction mixture isstirred at room temperature for one hour, then 700 mg of methyl2-alpha,-3-alpha-dihydroxy-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)cyclopentane-1β-carboxylate in 30 ml tetrahydrofuranis added. The reaction mixture is stirred at room temperature for twodays. The reaction mixture is treated with 14 ml acetic acid at roomtemperature and stirring is continued for two hours. The solvent isremoved under vacuum to afford an amorphous solid. The crude productmixture is separated by flash column chromatography on reverse phaseoctadecylsilane (C₁₈)-bonded silica packing, eluting with methanol:water(first 1:9, then 2:8, then 3:7) to yield 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-cyclopentane;NMR (CD₃ OD): 4.40 (1H,q), 3.9 (2H,dd), 3.6 (2H,dd), 2.4 (1H,m), 2.15 (1H,m), 1.28 (1H,m).

EXAMPLE 9

2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)cyclopentane(150 mg) is treated with 3.0ml phenethylamine and the mixture is heatedat 130° for 5.5 hours. The residue is triturated with an ethylether:water mixture. The layers are separated and the aqueous layer iscombined with the insoluble material and concentrated to an oil. Thecrude product mixture is separated by flash column chromatography onreverse phase C₁₈ -octadecylsilane (C₁₈)-bonded silica gel packing,eluting first with water, followed by 10%, 30%, 50% methanol in water toyield2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-phenylethylamino)-9-adenyl]cyclo pentane as a white solid; m.p. 149-150°; NMR (DMSO-d₆):7.75 (1H,s), 7.28 (5H,m), 6.7 (2H,bs), 6.22 (1H,t), 5.00 (1H,d), 4.69(1H,t), 4.53 (2H,m), 4.37 (2H,t), 3.84 (1 H,m).

EXAMPLE 10

a) To 2.5 g of(+)-4β-(5-amino-2,6-dichloro-4-pyrimidinyl-amino)-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamide is added 40ml triethyl orthoformate and 0.5 ml of concentrated hydrochloric acid atroom temperature. After stirring at room temperature for three hours thereaction mixture is concentrated under high vacuum to afford a yellowoil. The oil is dissolved in 100 ml of a saturated solution of ammoniain methanol, and heated at 65-70° in a steel pressure reactor overnight.The reaction mixture is cooled to room temperature and solvent removedunder vacuum to afford crude product. Chromatography on silica gel,eluting with methylene chloride followed by methylene chloridecontaining up to 10% of methanol, gives (+)-2-alpha-3-alpha-dimethylmethylenedioxy-4-β-(2-chloro-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide as a white amorphous solid; [alpha]²⁵ _(D+) 2.80° (c1.5, MeOH); NMR (CD₃ OD): 8.25 (1H,s), 5.05 (2H,m), 3.23 (2H,q), 2.94(1H,m)2.54 (2H,t), 1.58 (3H,s), 1.31 (3H,s), 1.12 (3H,t).

A mixture of 1.8 g of(+)-2-alpha-3-alpha-dimethylmethylenedioxy-4-β-(2-chloro-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide and 40 ml of 1N hydrochloric acid isheated at 60° for 3 hours. The solvent is removed under vacuum and theresidue triturated with methanol and ether, then collected and driedunder vacuum to give(-)-2-alpha-3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide hydrochloride; m.p. 190° dec.;[alpha]²⁵ _(D-) 8.70° (c 0.77, MeOH); NMR (CD₃ OD): 9.29 (1H,S), 4.48(1H,dt) 4.23 (1H,dt) 2.90 (1H,m), 2.70 (1H,m), 2.24 (1H,m), 1.16(3H,t).

b) Similarly prepared is (+)-2-alpha,3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide.

The optically active starting materials are prepared as follows:

Racemic4β-amino-2-alpha,3-alpha-dimethylmethylenedioxycyclopentane-1β-N-ethylcarboxamide(Example 5, 5.4 g) is combined with 8.90 g of (-)-dibenzoyl-L-tartaricacid monohydrate in 100 ml boiling ethanol and allowed to cool slowly toroom temperature. The crystals which form are collected, washed withcold ethanol and dried under vacuum to yield colorless needles;[alpha]²⁵ _(D-) 66.69° (c 1.09, CH₃ OH). The(-)-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-N-ethylcarboxamidedibenzoyl-L-tartrate salt is dissolved in water, the solution is treatedwith excess sodium bicarbonate and the solvent is removed under vacuum.The filtrate is triturated with ethyl acetate. The solids are filteredoff and the filtrate is concentrated under vacuum to give(-)-4β-amino-2-alpha,-3-alpha-dimethylmethylenedioxy-cyclopentane-1.beta.-N-ethyl carboxamide as a yellow oil; [alpha]²⁵ _(D-) 31.15° (c 2.27,MeOH); NMR (CDCl₃): 4.81 (1H,dd), 4.39 (1H,d), 3.26 (2H,m) 1.80 (1H,dt).

The filtrate from the crystallization of the levorotatory salt isconcentrated under vacuum and the residue treated with excess aqueoussodium bicarbonate. The solvent is removed under vacuum and the residueis triturated with ethyl acetate. The insoluble material is collectedand the filtrate concentrated under vacuum to give a yellow oil. The oilis combined with 4.00 g (+)-dibenzoyl-D-tartaric acid monohydrate in 90ml boiling ethanol and allowed to cool slowly to room temperature. Theresulting crystals are collected, washed with cold ethanol and driedunder vacuum to yield the dextrorotatory salt as colorless plates;[alpha]²⁵ _(D+) 68.41° (c 1.14) CD₃ OD); NMR (CDCl₃): 6.55 (1H,s), 4.81(2H,dd), 4.4 (2H,d), 3.5 (1H,s), 3.29 (2H,q), 2.77 (1H,m), 2.4 (1H,m),1.8 (1H,t), 1.48 (3H,s), 1.29 (3H,s), 1.13 (3H,t).

(+)-4β-Amino-2-alpha,3-alpha-dimethylmethylenedioxycyclopentane-1.beta.-N-ethylcarboxamidedibenzoyl-D-tartrate (7.04 g) is dissolved in water and treated withexcess NaHCO₃. The solvent is removed under vacuum and the residue istriturated with ethyl acetate. The solids are filtered off and thefiltrate concentrated under vacuum to afford(+)-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1.beta.-N-ethylcarboxamideas a yellow oil; [alpha]²⁵ _(D+) 32.26° (c 1.52, MeOH); NMR (CDCl₃):4.81 (1H,dd), 4.41 (1H,d), 3.29 (2H,m), 1.84 (1H,dt).

To a solution of 2.016 g of 5-amino-2,4,6-trichloropyrimidine and 2.32 gof(+)-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1.beta.-N-ethylcarboxamidein 40 ml n-butanol is added 2.8 ml of triethylamine and the resultingmixture is heated at reflux under nitrogen atmosphere overnight. Thereaction mixture is cooled to room temperature and the solvent removedunder vacuum. The residue is partitioned between ethyl acetate andwater. The ethyl acetate solution is extracted with saturated sodiumchloride solution, dried over magnesium sulfate and evaporated todryness to yield a dark amorphous solid. The crude product ischromatographed on silica gel eluting with ethyl acetate, hexane (1:2 to4:1) to give (+)-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-2-alpha,3-alpha-dimethylmethylenedioxycyclopentane-1β-N-ethylcarboxamide,as a white amorphous solid; [alpha ]²⁵ _(D+) 27.36° (c 1.2, MeOH); NMR(CDCl₃): 5.95 (1H,bs), 4.72 (2H,t), 4.51 (1H,d), 3.31 (2H,m), 2.84(1H,d), 2.55 (1H,m), 1.93 (1H,d), 1.49 (3H,s), 1.29 (3H,s), 1.18 (3H,t).

Similarly, condensation of 5-amino-2,4,6-trichloropyrimidine with thelevorotatory amine yields the corresponding levorotatory intermediate.

EXAMPLE 11

a) t-Butyl p-(2-aminoethyl)-phenylpropionate (3.12 g) is combined neatwith 500 mg of(-)-2-alpha,3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide, [alpha]_(D) ²⁵⁻ 8.70° (c 0.77, MeOH), and heatedat 120° under nitrogen atmosphere for five hours. The reaction mixtureis cooled to room temperature and triturated with ether. The insolublematerial is filtered off and dried under vacuum. The solid obtained istriturated with water and the insoluble material is collected and driedunder vacuum to yield2-alpha,3-alpha-dihydroxy-4β-[2-(p-(2-t-butoxycarbonylethyl)-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide as anoff-white solid; m.p. 215° dec., NMR (CDCl₃); 7.9 (1H,s), 7.13 (4H,q),4.68 (1H,q), 4.47 (1H,t), 4.32 (1H,t), 3.58 (2H,t), 3.23 (2H,q), 2.82(4H,m), 2.5 (2H,t), 1.4 (9,s), 1.14 (3H,t); such being an opticalantipode of the compound of formula IIa wherein R₂ ' representsp-(t-butoxycarbonylethyl)-phenethylamino, R₆ ' represents ethyl, and R₇and R₈ represent hydrogen.

b) Similarly prepared is the optical antipode derived from thecorresponding dextrorotatory starting material.

c) Similarly prepared is the racemic 2-alpha,3-alpha-dihydroxy-4β-[2-[p-(2-t-butoxycarbonylethyl)-phenethylamino]-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide,m.p. 206-208°, using the racemic starting material.

t-Butyl p-(2-aminoethyl)-phenylpropionate is prepared as follows:

p-Bromophenylacetonitrile (50 g), t-butyl acrylate (46 ml), palladium(II) acetate (575 mg) and tri-o-tolylphosphine (3.1 g) are combined with125 ml triethylamine in a steel pressure reactor and heated at 140° for16 hours. The reaction mixture is cooled to room temperature and pouredinto 500 ml 3N hydrochloric acid at 0°. The solids are extracted intoethyl acetate and the ethyl acetate solution is extracted with saturatedNaCl solution and dried over magnesium sulfate. The crude product istriturated with ether:hexane (1:1), filtered and dried under vacuum toyield t-butyl p-(cyanomethyl)-phenylacrylate; m.p. 80-82°; NMR (CDCl₃):7.5 (2H,d), 7.32 (2H,d), 6.39 (2H,d), 3.78 (2H,s), 1.52 (9H,s).

t-Butyl p-(cyanomethyl)-phenylacrylate (6.0 g) is combined with 600 mg10% palladium on carbon in 80 ml isopropanol and 24 ml 1N HCl andtreated with hydrogen at room temperature. After 8 hours at 3atmospheres pressure, the catalyst is filtered off and the filtrateconcentrated under vacuum. The residue is triturated with ether,filtered and dried under vacuum to afford t-butylp-(2-aminoethyl)-phenylpropionate hydrochloride as a white solid. Thehydrochloride salt is partitioned between ethyl acetate and 1N NaOH. Theethyl acetate extract is washed with a saturated NaCl solution and driedover MgSO₄. Filtration and concentration of the filtrate affords t-butylp-(2-aminoethyl)-phenylpropionate as a yellow oil; NMR (CDCl₃): 7.1(4H,s), 2.98 (2H,t), 2.89 (2H,t) 2.73 (2H,t), 2.5 (2H,t), 2.02 (2H,s),1.42 (9H,s).

EXAMPLE 12

a) Optically active2alpha,3-alpha-dihydroxy-4β-[2-[p-(2-t-butoxycarbonylethyl)-phenethylamino]-9-adenyl]-cyclopentane-1β-N-ethylcarboxamideexample 11a (160 mg) is treated with 20 ml of 1N HCl and heated at 60°for one hour. The solvent is removed under vacuum and the residuetriturated with ethanol, filtered off and dried under vacuum to give(-)2-alpha,3-alpha-dihydroxy-4β-[2-(p-(2-carboxyethyl)-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamidehydrochloride as a white solid; m.p. 243-245°; [alpha]_(D) ²⁵⁻ 4.34° (c0.99, DMSO); NMR (CD₃ OD): 8.11 (1H,s),7.18 (4H,q), 4.76 (1H,q), 4.5(1H,m), 4.28 (1H,m), 3.75 (2H,dt), 3.24 (2H,q), 2.94 (2H,t), 2.85(4H,t), 2.44 (4H,t), 2.3 (1H,m), 1.16 (3H,t); representing thelevorotatory antipode of the compound of formula IIa wherein R₂ 'represents p-(carboxyethyl)-phenethylamino, R₆ ' represents ethyl, andR₇ and R₈ represent hydrogen.

b) Similarly prepared is the corresponding dextrorotatory antipode, m.p.242-245°, [alpha]_(D) ²⁵ (DMSO)+3.48°.

c) Similarly prepared is also the corresponding racemic compound(example 7a), m.p. 235-237° from the ester precursor of Example 11Cwhich is obtained from racemic starting materials according to Examples10 and 11.

EXAMPLE 13

Treatment of(-)-2-alpha,3-alpha-dihydroxy-4β-[2-(p-carboxyethyl-2-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamidehydrochloride with ethanol and conc. sulfuric acid as catalyst underreflux overnight gives after workup (-)-2-alpha,3-alpha-dihydroxy-4β-[2-[2-(p-ethoxycarbonylethyl-phenethylamino)9-adenyl]-cyclopentane-1β-N-ethylcarboxamide; NMR (CD₃ OD): 4.05 (q,2H),1.29 (t,3H).

EXAMPLE 14

A mixture of 18 mg of2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentane (example 3), 100 mg of sodium hydrogen sulfide, and 0.5 mlof DMF is stirred at 140° overnight. The reaction mixture is cooled toroom temperature, neutralized with 0.1N HCl to PH 6, then concentratedunder reduced pressure to give crude2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-thio-9-adenyl)]-cyclopentane.The crude product is dissolved in a mixture of 3 ml ethanol, 1 ml 0.25Nsodium hydroxide, 0.5 ml allyl bromide and the mixture is stirred atroom temperature for 20 hours. The reaction mixture is poured intowater, neutralized with 0.1N HCl to pH 7, then concentrated underreduced pressure to yield an amorphous solid. Flash chromatography ofthe crude product on a reverse phase C₁₈ -column, eluting withwater:methanol (3:2) affords2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-allylthio-9-adenyl)]-cyclopentane m.p. 126-128°, NMR (CD₃ OD): 8.2 (1H,s), 6.0 (1H,m), 5.3(1H,dd), 5.1 (1H,dd), 4.75 (1H,m), 4.58 (1H,m), 4.05 (1H,dd), 3.8(1H,m), 3.67 (1H,m), 2.4 (1H,m), 2.24 (1H,m), 2.02 (1H,m).

EXAMPLE 15

Treatment of2-alpha,3-alpha-diacetoxy-4β-[2-(2-phenylethylamino)-6-chloro-9-purinyl])-cyclopentane-1β-N-ethylcarboxamide with saturated methanolic ammonia at100° in a sealed tube yields2-alpha,3-alpha-dihydroxy-4β-[2-(2-phenylethylamino)-9-adenyl]-cyclopentane-1β-N-ethyl-carboxamide of example 2a.

The starting material is prepared as follows:

To a solution of 740 mg of2-alpha,3-alpha-dimethylmethylenedioxy-4β-(5-amino-2,6-dichloro-4-pyrimidinyl-amino)-cyclopentane-1β-N-ethylcarboxamidein 10 ml triethyl orthoformate is added 0.15 ml concentratedhydrochloric acid at room temperature. The reaction mixture is stirredfor 18 hours, then concentrated under reduced pressure to give an oil. Asolution of the oil in n-butanol is then heated at reflux for 4 hoursand cooled. All the volatiles are evaporated to yield crude productwhich is then purified by flash chromatography on silica gel. Elutingwith 4% methanol in methylene chloride gives2-alpha,-3-alpha-dimethylmethylenedioxy-4β-(2,6-dichloro-9-purinyl)cyclopentane-1β-N-ethylcarboxamide; NMR(CD₃ OD/CDCl₃): 8.2(1H,s), 2.1-2.9(3H,m).

A solution of 60 mg of2-alpha,3-alpha-dimethylmethylenedioxy-4β-(2,6-dichloro-9-purinyl)-cyclopentane-1β-N-ethylcarboxamide in 5 ml 1 N HCl is heated to refluxfor 5 hours and cooled. The reaction mixture is concentrated underreduced pressure to give crude product. The crude product is dissolvedin 3 ml of methanol, 0.1 ml of phenylethylamine is added and thesolution is heated under reflux for 5 hours. After the reaction iscomplete, all the volatiles are evaporated. The resulting crude solid ispurified by chromatography on a reverse phase (C₁₈) packing, elutingwith water:methanol (8:1 to 5:1) to give2-alpha,3-alpha-dihydroxy-4β-[2-(2-phenylethylamino)-6-hydroxy-9purinyl]-cyclopentane-1β-N-ethylcarboxamide;NMR(CD₃ OD): 8.3(1H,s), 7.2-7.4(5H,m), 4.85(1H,q), 4.45(1H,dd),4.3(1H,dd), 3.15(1H,t), 2.95(1H,t), 2.84(1H,m), 2.62(1H,m), 2.2(1H,m).

Selective acetylation using a procedure as illustrated for a similartransformation in Canadian J. Chem. 59, 2601 (1981) yields2-alpha,3-alpha-diacetoxy-4β-[2-(2-phenylethylamino)-6-hydroxy-9-purinyl]-cyclopentane-1β-N-ethylcarboxamide.

Treatment with phosphorus oxychloride and N,N-diethylaniline yields2-alpha-3-alpha-diacetoxy-4β-[2-(2-phenylethylamino)-6-chloro-9-purinyl]-cyclopentane-1β-N-ethylcarboxamide.

EXAMPLE 16

a)2-alpha-3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1-.beta.-N-ethylcarboxamide(100 mg) is treated with 1.0 ml 2-cyclohexylethylamine, neat and heatedat 120° C. for four hours. The reaction mixture is concentrated todryness under high vacuum and the residue triturated with ether. Theinsoluble material is filtered and then triturated with water. The waterinsoluble material is filtered and dried under high vacuum. The crudeproduct mixture is purified by flash column on silica gel, eluting withdichloromethane followed by 10% methanol in dichloromethane to yield2-alpha-3-alpha-dihydroxy-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamideof example 7j, m.p. 228-232°.

b) Similarly condensation of(-)-2-alpha-3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)-cyclopentane-1.beta.-N-ethylcarboxamideof example 10(a) with 2-cyclohexylethylamine yields the correspondingantipode of2-alpha-3-alpha-dihydroxy-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide,m.p. 250° dec; [alpha]²⁵ _(D-) 9.66° (2.9 mg/ml, DMSO).

c)2-alpha,3-alpha-dihydroxy-4β-(2-chloro-9-adenyl)cyclo-pentane-1-.beta.-N-ethylcarboxamide(50mg) and 0.5 ml of aniline, are heated for 4 hours at 150° in a sealedtube. The resulting mixture is cooled, concentrated to dryness andfiltered through a short path reverse phase (C₁₈) column, eluting firstwith water, followed by 2:1 water:acetonitrile. The obtained material isfurther purified once more through a reverse phase (C₁₈) column, elutingfirst with water, followed by 3:1 water:acetonitrile.2-alpha-3-alpha-Dihydroxy-4β-(2-anilino-9-adenyl)-cyclopentane-1-.beta.-N-ethylcarboxamide is obtained; m.p. 259.5-260.5° (dec); dextrorotatoryHCl salt, [alpha]_(D) ²⁵⁺ 3.77° (c 1.0, DMSO), m.p. 270° dec, preparedfrom levorotatory 2-chloro compound as under b).

EXAMPLE 17

The following compounds are prepared substantially according toprocedures described herein:

a) 2-alpha,3-alpha-dihydroxy-4β-[2-chloro-N₆-(2-N-pyrrolylcyclohexyl)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide,m.p. above 150° dec;

b)3-alpha-hydroxy-4β-[2-(3-phenylpropylamino)-9-adenyl]-cyclopentane-1-β-N-ethylcarboxamide, m.p. 185-186°;

c)3-alpha-hydroxy-1β-hydroxymethyl-4β-[2-(2-phenylpropylamino)-9-adenyl]-cyclopentane;

d)2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-phenethylthio)-9-adenyl]cyclopentane;

e)2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2[p-(2-carboxyethyl)-phenethylamino]-9-adenyl]-cyclopentane;

f)2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-anilino-9adenyl)-cyclopentane,m.p. 266-270°.

g)2-alpha,3-alpha-dihydroxy-4β-(2-cyclohexylamino-9-adenyl)-cyclopentane-1β-N-ethylcarboxamide,m.p. 228-229.5°;

h) 2-alpha,3-alpha-dihydroxy-4β-[2-(3-pyridylamino)-9-adenyl]-cyclopentane-1.beta.-N-ethylcarboxamide, m.p. 193-195° dec.;

i) (+)-2-alpha,3-alpha-dihydroxy-4β-[2-(m-ethoxycarbonylanilino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide,m.p. 249-250°; chiral dihydrate m.p. 265° dec., [alpha]²⁵ _(D+) 8.79° (c1.0, DMSO), prepared from levorotatory 2-chloro compound;

j) (+)-2-alpha,3-alhpa-dihydroxy-4β-[2-(p-ethoxycarbonylamilino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide, m.p. 283-285° dec.; chiral, m.p. 273-277°,[alpha]²⁵ _(D) + 6.11° (c 1.1, DMSO), prepared from levorotatory2-chloro compound;

k) 2-alpha,3-alpha-dihydroxy-4β-[2-(p-methylanilino)-9-adenyl]-cyclopentane-1.beta.-N-ethylcarboxamide, m.p. above 250°;

1) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane,m.p. 177-180°;

m) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(m-ethoxycarbonylanilino)-9-adenyl]-cyclpentane;

n) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(p-ethoxycarbonylanilino)-9-adenyl]-cyclopentane;NMR (CD₃ OD); 4.35 (2H,q), 4.05 (2H,m), 1.40 (3H,t);

o) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(4-carboxycyclohexylamino)-9-adenyl]-cyclopentane;

p) 2-alpha,3-alpha-dihydroxy-4β-[2-(4-carboxyethylcyclohexylethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide; starting material can be prepared byhydrogenation of t-butyl p-(2-aminoethyl)-phenyl propionate in aceticacid in the presence of platinum catalyst;

q) 2-alpha,3-alpha-dihydroxy-4β-[2-(p-cyanoanilino)-9adenyl]-cyclopentane-1.beta.-N-ethylcarboxamide;

r) 2-alpha,3-alpha-dihydroxy-4β-[2-(tetrahydropyran-4-yl)-ethylamino-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide; the starting2-(tetrahydro-pyran-4-yl)-ethylamine can be prepared fromtetrahydropyran-4-one e.g. by Wittig condensation with diethylcyanomethyl phosphonate followed by hydrogenation and reduction withlithium aluminum hydride;

s) 2-alpha,3-alpha-dihydroxy-4β-[2-(1-adamantyl)-ethylamino-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide.

EXAMPLE 18

a) (-)-2-alpha,3-alpha-Dimethylmethylenedioxy-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-1β-hydroxymethylcyclopentane, 180 mg, is treated with 3.0 ml triethylorthoformate and 0.05 ml conc. HCl, then stirred at room temperature for1.5 hours. The reaction mixture is concentrated under vacuum to give anoil [alpha]_(D) ²⁵⁼⁻ 17.03° (c 1.18; MeOH). The oil is dissolved in 4 mlof methanol saturated with ammonia, placed in a sealed tube and heatedat 65° for 15 hours. The solvent is removed under vacuum, and residue isheated in 6 ml 1N HCl at 60-70° for two hours. The solvent is removedunder vacuum and the product mixture purified on a reverse phase C₁₈flash column, eluting with water followed by 5% MeOH/water, then 10%MeOH/water and finally 20% MeOH/water, to yield the levorotatoryenantiomer of the compound of example 8; (-)-2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl- 4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride, as a white solid, m.p. 184-187°; [alpha]_(D) ²⁵⁼⁻ 40.38°(c 1.05, MeOH); NMR (CD₃ OD): 8.20 (1H,s), 4.79 (1H,q), 4.48 (1H,dd),4.20 (1H,dd), 2.45 (1H,m), 2.24 (1H,m), 1.90 (1H,m);

The starting material is prepared as follows:

5,6-Dihydroxy-2-azabicyclo[2.2.1]-heptan-3-one, 14.0 g, is heated atreflux in 200 ml saturated HCl in ethanol for two hours. The reactionmixture is cooled to room temperature and the solvent removed undervacuum to give ethyl 4β-amino-2-alpha,3-alpha-dihydroxycyclopentane-1β-carboxylate hydrochloride as an oil,NMR (CD₃ OD): 4.20 (2H,q), 3.90 (1H,dd), 3.49 (1H,q), 2.90 (1H,m), 2.45(1H,m), 1.82 (1H,m), 1.18 (3H,t).

A solution of 26.9 g of ethyl 4β-amino-2-alpha,3-alpha-dihydroxy-cyclopentane-1β-carboxylate and 33.2 ml triethylaminein 150 ml CH₂ Cl₂ is cooled to 0° and a solution of 17.2 ml benzylchloroformate in 20 ml CH₂ Cl₂ is added dropwise over 20 minutes. Thereaction mixture is allowed to warm slowly to room temperature, thenstirred at room temperature for 15 hours. The solvent is removed undervacuum and the residue dissolved in ethyl acetate. The ethyl acetatesolution is extracted with water, 1N HCl, sat. NaHCO₃, sat. NaCl, driedover MgSO₄ and evaporated to dryness. Purification of the crude productby flash column chromatography on silica gel eluting with EtOAc: hexane(1:2) and then with EtOAc affords ethyl N-Cbz-4β-amino-2-alpha,3-alpha-dihydroxycyclopentane-1β-carboxylate as an oil; NMR (CDCl₃),7.36 (5H,s), 5.39 (1H,d), 5.09 (2H,d), 4.27 (1H,t), 4.15 (2H,q), 4.11(1H,m), 3.99 (1H,m), 3.92 (1H,q), 2.90 (1H,m), 2.46 (1H,m), 1.69 (1H,m),1.27 (3H,t); Cbz=benzyloxycarbonyl, also called carbobenzyloxy.

To a solution of 9.4 g ethyl N-Cbz-4β-amino-2-alpha,3-alpha-dihydroxycyclopentane-1β-carboxylate in 150 ml acetone is added35.7 ml 2,2-dimethoxypropane and 673 mg camphorsulfonic acid. Thereaction mixture is stirred at room temperature for 3 1/2 hours. Thesolvent is removed under vacuum and the residue dissolved in CH₂ CH₂ andextracted with sat. NaHCO₃, sat. NaCl solution , dried over MgSO₄ andevaporated to dryness to yield ethyl N-Cbz-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-carboxylate as a whitecrystalline solid; NMR (CDCl₃) 7.33 (5H,s), 5.80 (1H,bd), 5.10 (2H,d),4.82 (1H,d), 4.51 (1H,d), 4.17 (2H,q), 3.00 (1H,d), 2.43 (1H,m), 1.95(1H,d), 1.49 (3H,s), 1.30 (2H,s), 1.28 (3H,t).

Calcium chloride, 5.74 g, and 3.9 g NaBH₄ are combined in 350 ml dry THFand stirred at room temperature for one hour. A solution of 9.4 g ethylN-Cbz-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-cyclopentane-1β-carboxylate in 100 ml THFis added in one portion. The reaction mixture is stirred at roomtemperature for two days, then cooled to 0° and 100 ml glacial aceticacid added dropwise. The reaction mixture is then stirred at roomtemperature for 2 1/2 hours. The solvent is removed under vacuum and theresidue partitioned between EtOAc and sat. NaHCO₃. The organic phase iswashed with sat. NaCl, dried over MgSO₄, and evaporated to dryness.Purification of the crude product by flash column chromatography onsilica gel eluting with 10% MeOH in CH₂ Cl₂ affordsN-Cbz-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-1β-hydroxymethyl-cyclopentane as an oil;NMR (CDCl₃): 7.34 (5H,s), 5.90 (1H,bs), 5.10 (2H,s), 4.56 (1H,dd), 4.40(1H,d), 4.12 (1H,bm), 3.81 (1H,dd), 3.65 (1H,dd), 3.50 (1H,s), 2.50(1H,m), 2.30 (1H,m), 2.20 (1H,s), 1.48 (3H,s), 1.30 (3H,s).

A solution of 7.73 g N-Cbz-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-1β-hydroxymethyl -cyclopentane in 70 mlEtOH is treated with 700 mg 10% Pd on carbon and hydrogenated at roomtemperature and 3 atmospheres pressure for two hours. The catalyst isfiltered off and the filtrate concentrated under vacuum to afford4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-1β-hydroxymethylcyclopentane as an oil;NMR (CDCl₃): 4.80 (1H,d), 4.30 (1H,d), 3.75 (2H,m), 3.52 (4H,m), 2.46(1H,m), 1.45 (3H,s), 1.28 (3H,s).

A solution of 4.4 g 4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-1β-hydroxymethyl-cyclopentane in 175 mlEtOH is treated with 8.84 g dibenzoyl-D-tartaric acid monohydrate. Theresulting suspension is heated to boiling and insoluble material removedby filtration. The filtrate is allowed to cool slowly to roomtemperature to afford the dextrorotatory crystaline dibenzoyl-D-tartratesalt, m.p. 205-210° C., [alpha]_(D) ²⁵⁼⁺ 75.43° (c 0.94, MeOH) Treatingthe salt with excess NaHCO₃ solution, removing the solvent, thentreating the residue with EtOAc affords(+)-4-β-amino-2-alpha-3-alpha-dimethylmethylenedioxy-1β-hydroxymethylcyclopentane,[alpha]_(D) ²⁵⁼⁺ 41.60° (c 0.8, MeOH).

(+)-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy1β-hydroxymethylcyclopentane, 145 mg, iscombined with 153 mg 5-amino-2,4,6-trichloropyrimidine and 0.2 mltriethylamine in 10 ml n-BuOH and heated at reflux under nitrogenatmosphere for 15 hours. The solvent is removed under vacuum and productmixture is purified by flash column chromatography on silica gel elutingwith EtOAc: hexane (1:1), then with EtOAc, to yield (-)-2-alpha,3-alpha-dimethylmethylenedioxy-4β-(5-amino-2,6-dichloro-4-pyrimidinylamino)-2β-hydroxymethylcyclopentane as an amorphous solid; m.p. 60-65°; [alpha]_(D) ²⁵⁼⁻ 32.30°(c. 0.8, MeOH); NMR (CDCl₃): 4.70 (1H,d), 4.62 (1H,m), 4.45 (1H,d), 3.99(1H,dd), 3.77 (1H,dd), 2.70 (1H,m), 2.43 (1H,m), 1.73 (1H,d), 1.52(3H,s), 1.32 (3H,s).

b) Similarly prepared is (+)-2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl) -cyclopentaneusing (-)-4β-amino-2-alpha,3-alpha-dimethylmethylenedioxy-1β-hydroxymethyl-cyclopentane asreactant.

EXAMPLE 19

a) Racemic 2-alpha,3-alpha-dihydroxy-1β-hydroxy-methyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride, 50 mg, is treated with 0.5 ml 2-cyclohexylethylamine andheated at 130° C. under N₂ for 15 hours. The reaction mixture is cooledto room temperature and triturated with ether. The insoluble material isfiltered off and air-dried. The solid is triturated with water and againwith ether to afford a solid. The crude product is purified by flashcolumn chromatography on C₁₈ reverse phase packing, eluting withacetonitrile: water first (1:3), then (1:1) to yield 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-cyclohexylethylamino)-9-adenyl]cyclopentane,as white solid, m.p. 177-180°; NMR (CD₃ OD): 7.78 (1H,s), 4.64 (1H,q),4.53 (1H,m), 4.03 (1H,m), 3.68 (2H,m), 2.40 (1H,m), 2.22 (1H,m), 1.99(1H,m), 1.75 to 1.00 (15H,m).

b) Similarly prepared from (-)-2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride is the corresponding (-)-2-alpha,3-alpha0dihydroxy-1β-hydroxymethyl-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane;[alpha]_(D) ²⁵⁻ 26.75° (c 0.83, methanol).

EXAMPLE 20

a) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride, 50 mg is treated with 0.25 ml freshly distilled anilineand heated to 130° under nitrogen atmosphere for 15 hours. The reactionmixture is cooled to room temperature and triturated with ether. Theinsoluble material is filtered off, air-dried and then triturated withwater. The insoluble material is filtered off and dried underhigh-vacuum to yield 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-anilino-9-adenyl) -cyclopentaneas an off-white solid, m.p. 266-270°; NMR (CD₃ OD): 8.06 (1H,s), 7.62(2H,d), 7.35 (2H,t), 7.05 (1H,t), 4.72 (1H,q), 4.55 (1H,dd), 4.01(1H,dd), 3.64 (2H,m), 2.39 (1H,m), 2.21 (1H,m), 2.04 (1H,m).

b) Similarly prepared from (-)-2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride is the optically active 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-anilino-9-adenyl)-cyclopentane.

EXAMPLE 21

a) 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentanehydrochloride, 35 mg, is combined with 172 mg of ethyl p-aminobenzoateand heated in a sealed tube at 140° for 15 hours. The reaction mixtureis cooled to room temperature and triturated with ether. The insolublematerial is filtered off and air-dried, then triturated with water. Theinsoluble material is filtered off, washed with ether and dried undervacuum to yield 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(p-ethoxycarbonylanilino)-9-adenyl]-cyclopentane; NMR (CD₃ OD) 8.10 (1H,s), 7.98 (2H,d), 7.83(2H,d), 4.60 (1H,dd), 4.48 (1H,dd), 4.35 (2H,q), 4.05 (2H,m), 2.43(1H,m), 2.25 (1H,m), 2.10 (1H,m), 1.40 (3H,t).

b) Similarly prepared from (-)-2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-chloro-9-adenyl)-cyclopentane;hydrochloride is the optically active 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(p-ethoxycarbonylanilino-9-adenyl]-cyclopentane.

EXAMPLE 22

(-)-2-alpha,3-alpha-dihydroxy-4β-[2-(p-carboxyethyl-2-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamideis converted to the sodium salt. A mixture of 0.65 g of the sodium saltand 160 mg of ethyl iodide in 10 ml of dimethylformamide is stirred atroom temperature overnight. The reaction mixture is poured into waterand the product extracted with ethyl acetate to yield (-)-2-alpha,3-alpha-dihydroxy-4β-[2-[p-ethoxycarbonylethyl-2-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethlcarboxamide.

EXAMPLE 23

A) Preparation of 10,000 tablets each containing 10 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        2-alpha,3-alpha-dihydroxy-4β-(9-adenyl)-                                                          100.00   g                                           cyclopentane-1β-N-ethylcarboxamide                                       Lactose                  2,400.00 g                                           Corn starch              125.00   g                                           Polyethylene glycol 6,000                                                                              150.00   g                                           Magnesium stearate       40.00    g                                           Purified water           q.s                                                  ______________________________________                                    

Procedure

All the powders are passed through a screen with openings of 0.6mm. Thenthe drug substance, lactose, magnesium stearate and half of the starchare mixed in a suitable mixer. The other half of the starch is suspendedin 65ml of water and the suspension added to the boiling solution of thepolyethylene glycol in 260 ml of water. The paste formed is added to thepowders, which are granulated, if necessary, with an additional amountof water. The granulate is dried overnight at 35°, broken on a screenwith 1.2 mm openings and compressed into tablets, using concave punchesuppers bisected.

b) Preparation of 1,000 capsules each containing 10 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        2-alpha,3-alpha-dihydroxy-4β-[2-(2-phenyl-                                                         10.0    g                                           ethylamino)-9-adenyl]-cyclopentane-1β-N-ethyl-                           carboxamide                                                                   Lactose                   207.0   g                                           Modified starch           80.0    g                                           Magnesium stearate        3.0     g                                           ______________________________________                                    

Procedure

All the powders are passed through a screen with openings of 0.6mm. Thenthe drug substance is placed in a suitable mixer and mixed first withthe magnesium stearate, then with the lactose and starch untilhomogeneous. No. 2 hard gelatin capsules are filled with 300 mg of saidmixture each, using a capsule filling machine.

c) Similarly prepared are capsules and tablets of the other compoundsdisclosed herein, e.g. of2-alpha,3-alpha-dihydroxy-4β-[2-(p-carboxyethyl-phenethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamidehydrochloride,2-alpha,3-alpha-dihydroxy-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane-1β-N-ethylcarboxamide, 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-(2-anilino-9-adenyl)-cyclopentane,2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentane.

What is claimed is:
 1. A compound of the formula ##STR21## wherein R₂ 'represents NR_(b) '--R₁ ' or NHR₁ '; R₁ ' represents cyclohexenyl-loweralkyl, C₃ -C₆ -cycloalkyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl,4-tetrahydropyranyllower alkyl, 4-tetrahydrothiopyranyl-lower alkyl,admantyl-lower alkyl, C₃ -C₆ -cycloalkyl-lower alkyl, aryl or aryl-loweralkyl in which aryl represents thienyl, pyridyl, phenyl or phenylsubstituted by one to three of halogen, trifluoromethyl, lower alkoxy,lower alkyl or by a substituent --W--Z in which W represents a directbond, lower alkylene or oxy-lower alkylene, and Z represents hydroxy,cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-loweralkylcarbamoyl; or R₁ ' represents a substituent of the formula B'##STR22## in which A' represents a direct bond, methylene, oxy or thio,p represents zero, one or two, and R_(a) ' represents hydrogen, loweralkyl, lower alkoxy or halogen; R₃ ' represents hydrogen or hydroxy;R_(b) ' represents lower alkyl; a pharmaceutically acceptable prodrugester derivative thereof in which one or more free hydroxy groups areesterified in for of a pharmaceutically acceptable ester; or apharmaceutically acceptable salt thereof.
 2. A compound of the formula##STR23## wherein R₂ ' represents NH(CH₂)_(n) --(C₅ or C₆)-cycloalkyl,NR_(b) '--(CH₂)_(n) --(C₅ or C₆)-cycloalkyl, NH(CH₂)_(n) --Ar or 1,2 or3, R_(b) ' represents C₁ -C₃ -alkyl, and Ar represents 2-, 3- or4-pyridyl, phenyl or phenyl substituted by one or two of halogen,trifluoromethyl, lower alkoxy, lower alkyl or by a substituent --W--Z inwhich W represents a direct bond, straight chain C₁ -C₄ -alkylene oroxy-C₁ -C₃ -alkylene and Z represents hydroxy, cyano, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R₇,R₇ ' and R₈ independently represent hydrogen, lower alkanoyl, loweralkoxy-lower alkanoyl, aroyl, carbamoyl, mono- or di-loweralkylcarbamoyl; or a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 2 wherein R₂ ' represents NH-Ar in which Arrepresents 2-, 3- or 4-pyridyl, phenyl or phenyl substituted by halogen,trifluoromethyl, lower alkoxy, lower alkyl, cyano, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl; R₇,R₇ ' and R₈ independently represent hydrogen, lower alkanoyl or loweralkoxy-lower alkanoyl; or a pharmaceutically acceptable salt thereof. 4.A compound according to claim 1 of the formula ##STR24## wherein R₇, R₇' and R₈ represent hydrogen or lower alkanoyl; R₉ represents hydrogen ormethyl; R₁₀ represents hydrogen or methyl; R₁₁ represents1-cyclohexenyl, cyclohexyl or cyclohexyl substituted by lower alkyl,hydroxy, lower alkoxy or by a substituent W--Z in which W represents adirect bond, CH₂ or CH₂ CH₂, and Z represents carboxy or loweralkoxycarbonyl; or R₁₁ represents 2-, 3-or 4-pyridyl, phenyl or phenylmonosubstituted by halogen, lower alkyl, lower alkoxy or W--Z wherein Zrepresents carboxy or lower alkoxycarbonyl and W represents a directbond, CH₂ or CH₂ CH_(2;) or a pharmaceutically acceptable salt thereof.5. A compound according to claim 4 wherein R₉ and R₁₀ represent hydrogenor a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 4 being 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(2-cyclohexylethylamino)-9-adenyl]-cyclopentaneor a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 4 being 2-alpha,3-alpha-dihydroxy-1β-hydroxymethyl-4β-[2-(p-ethoxycarbonylanilino)-9-adenyl]-cyclopentaneor a pharmaceutically acceptable salt thereof.
 8. A compound of theformula ##STR25## wherein R, R₃ and R₅ on dependently represent hydrogenor hydroxy provided that at least one of R, R₃ and R₅ representshydroxy; R₁ represents hydrogen or lower alkyl; or R₁ representsaryl-lower alkyl wherein aryl represents phenyl, phenyl substituted byhalogen, trifluoromethyl, lower alkoxy, lower alkyl or by a substituent--W--Z in which W represents a direct bond, lower alkylene, or oxy-loweralkylene, and Z represents cyano, carboxy, carboxy derivatized in theform of a pharmaceutically acceptable ester or carboxy derivatized inthe form of a pharmaceutically acceptable amide; R₂ represents halogenor --SR₁ ' in which R₁ ' has meaning as defined for R₁ provided that R₁' does not represent hydrogen; R₄ represents lower alkoxymethyl or loweralkylthiomethyl; or R₄ represents hydroxymethyl; a pharmaceuticallyacceptable ester derivative thereof in which one or more free hydroxygroups are esterified in form of a pharmaceutically acceptable ester; ora pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition having adenosine-2-receptor stimulating activity suitablefor administration to a mammal comprising an effective amount of acompound of claim 1 in combination with one or more pharmaceuticallyacceptable carriers.
 10. A method of stimulating adenosine-2 receptorsin mammals comprising the administration to a mammal in need thereof ofan effective amount of a compound of claim 1 or of a pharmaceuticalcomposition comprising said compound.
 11. A method of treatingcardiovascular conditions responsive to adenosine-2 receptor stimulationin mammals comprising the administration to a mammal in need thereof ofan effective adenosine-2 receptor stimulating amount of a compound ofclaim 1 or of a pharmaceutical composition comprising a said compound.12. A method of treating hypertension in mammals comprising theadministration to a mammal in need thereof of an effectiveantihypertensive amount of a compound of claim 1 or of a pharmaceuticalcomposition comprising a said compound.